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1

Qiu, Yuan, Aimin Pu, Hong Zheng, Minqiang Liu, Weigang Chen, Wensheng Wang, Weidong Xiao, and Hua Yang. "TLR2-Dependent Signaling for IL-15 Production Is Essential for the Homeostasis of Intestinal Intraepithelial Lymphocytes." Mediators of Inflammation 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/4281865.

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TLR2 signaling is related to colitis and involved in regulation of innate immunity in the intestinal tract, but the mechanisms remain unclear. The aim of this study is to investigate how TLR2 affects differentiation of intraepithelial lymphocytes (IELs) and regulates the susceptibility of colitis. IELs were isolated from the small intestine and colon of mice, respectively. The IEL phenotype, activation, and apoptosis were examined using flow cytometry and RT-PCR. IL-15 expression and IEL location were detected through immunohistochemistry. The experimental colitis was induced by administration of dextran sulfate sodium (DSS). We found that the numbers of CD8αα+, CD8αβ+, and TCRγδ+IELs were significantly decreased in TLR2-deficient mice and the residual IELs displayed reduced activation and proliferation and increased apoptosis, accompanied with impaired IL-15 expression by intestinal epithelial cells (IECs). Further study showed that TLR2 signaling maintained the expression of IL-15 in IEC via NF-κB activation. Moreover, TLR2-deficient mice were found to be more susceptible to DSS-induced colitis as shown by the increased severity of colitis. Our results demonstrate that IECs contribute to the maintenance of IELs at least partly via TLR2-dependent IL-15 production, which provides a clue that may link IECs to innate immune protection of the host via IELs.
2

Hummel, Jonas F., Patrice Zeis, Karolina Ebert, Jonas Fixemer, Philip Konrad, Christian Schachtrup, Sebastian J. Arnold, Dominic Grün, and Yakup Tanriver. "Single-cell RNA-sequencing identifies the developmental trajectory of C-Myc-dependent NK1.1− T-bet+ intraepithelial lymphocyte precursors." Mucosal Immunology 13, no. 2 (November 11, 2019): 257–70. http://dx.doi.org/10.1038/s41385-019-0220-y.

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Abstract Natural intraepithelial lymphocytes (IELs) are thymus-derived adaptive immune cells, which are important contributors to intestinal immune homeostasis. Similar to other innate-like T cells, they are induced in the thymus through high-avidity interaction that would otherwise lead to clonal deletion in conventional CD4 and CD8 T cells. By applying single-cell RNA-sequencing (scRNA-seq) on a heterogeneous population of thymic CD4−CD8αβ−TCRαβ+NK1.1− IEL precursors (NK1.1− IELPs), we define a developmental trajectory that can be tracked based on the sequential expression of CD122 and T-bet. Moreover, we identify the Id proteins Id2 and Id3 as a novel regulator of IELP development and show that all NK1.1− IELPs progress through a PD-1 stage that precedes the induction of T-bet. The transition from PD-1 to T-bet is regulated by the transcription factor C-Myc, which has far reaching effects on cell cycle, energy metabolism, and the translational machinery during IELP development. In summary, our results provide a high-resolution molecular framework for thymic IEL development of NK1.1− IELPs and deepen our understanding of this still elusive cell type.
3

Kooy-Winkelaar, Yvonne M. C., Dagmar Bouwer, George M. C. Janssen, Allan Thompson, Martijn H. Brugman, Frederike Schmitz, Arnoud H. de Ru, et al. "CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes." Proceedings of the National Academy of Sciences 114, no. 6 (January 3, 2017): E980—E989. http://dx.doi.org/10.1073/pnas.1620036114.

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Refractory celiac disease type II (RCDII) is a severe complication of celiac disease (CD) characterized by the presence of an enlarged clonal population of innate intraepithelial lymphocytes (IELs) lacking classical B-, T-, and natural killer (NK)-cell lineage markers (Lin−IELs) in the duodenum. In ∼50% of patients with RCDII, these Lin−IELs develop into a lymphoma for which no effective treatment is available. Current evidence indicates that the survival and expansion of these malignant Lin−IELs is driven by epithelial cell-derived IL-15. Like CD, RCDII is strongly associated with HLA-DQ2, suggesting the involvement of HLA-DQ2–restricted gluten-specific CD4+ T cells. We now show that gluten-specific CD4+ T cells isolated from CD duodenal biopsy specimens produce cytokines able to trigger proliferation of malignant Lin−IEL lines as powerfully as IL-15. Furthermore, we identify TNF, IL-2, and IL-21 as CD4+ T-cell cytokines that synergistically mediate this effect. Like IL-15, these cytokines were found to increase the phosphorylation of STAT5 and Akt and transcription of antiapoptotic mediator bcl-xL. Several small-molecule inhibitors targeting the JAK/STAT pathway blocked proliferation elicited by IL-2 and IL-15, but only an inhibitor targeting the PI3K/Akt/mTOR pathway blocked proliferation induced by IL-15 as well as the CD4+ T-cell cytokines. Confirming and extending these findings, TNF, IL-2, and IL-21 also synergistically triggered the proliferation of freshly isolated Lin−IELs and CD3−CD56+ IELs (NK-IELs) from RCDII as well as non-RCDII duodenal biopsy specimens. These data provide evidence implicating CD4+ T-cell cytokines in the pathogenesis of RCDII. More broadly, they suggest that adaptive immune responses can contribute to innate IEL activation during mucosal inflammation.
4

Jiang, Wei, Xiaqiong Wang, Benhua Zeng, Lei Liu, Aubry Tardivel, Hong Wei, Jiahuai Han, et al. "Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes." Journal of Experimental Medicine 210, no. 11 (September 23, 2013): 2465–76. http://dx.doi.org/10.1084/jem.20122490.

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NOD2 functions as an intracellular sensor for microbial pathogen and plays an important role in epithelial defense. The loss-of-function mutation of NOD2 is strongly associated with human Crohn’s disease (CD). However, the mechanisms of how NOD2 maintains the intestinal homeostasis and regulates the susceptibility of CD are still unclear. Here we found that the numbers of intestinal intraepithelial lymphocytes (IELs) were reduced significantly in Nod2−/− mice and the residual IELs displayed reduced proliferation and increased apoptosis. Further study showed that NOD2 signaling maintained IELs via recognition of gut microbiota and IL-15 production. Notably, recovery of IELs by adoptive transfer could reduce the susceptibility of Nod2−/− mice to the 2,4,6-trinitrobenzene sulfonic acid (TNBS)–induced colitis. Our results demonstrate that recognition of gut microbiota by NOD2 is important to maintain the homeostasis of IELs and provide a clue that may link NOD2 variation to the impaired innate immunity and higher susceptibility in CD.
5

Losurdo, Giuseppe, Domenico Piscitelli, Federica Pezzuto, Francesco Fortarezza, Claudia Covelli, Antonella Marra, Andrea Iannone, et al. "T Helper Lymphocyte and Mast Cell Immunohistochemical Pattern in Nonceliac Gluten Sensitivity." Gastroenterology Research and Practice 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/5023680.

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Background and Aims. Nonceliac gluten sensitivity (NCGS) is a gluten-related emerging condition. Since few data about NCGS histopathology is available, we assessed the markers of lymphocyte and innate immunity activation. Materials and Methods. We retrieved duodenal biopsy samples of patients with NCGS diagnosis according to the Salerno criteria. We selected specimens of positive (seropositive celiac disease/Marsh 1-2 stage) and negative (normal microscopic picture) controls. Immunohistochemistry for CD3 (intraepithelial lymphocytes-IELs), CD4 (T helper lymphocytes), CD8 (T cytotoxic lymphocytes), and CD1a/CD117 (Langerhans/mast cells) was performed. ANOVA plus Bonferroni’s tests were used for statistical analysis. Results. Twenty NCGS, 16 celiac disease, and 16 negative controls were selected. CD3 in NCGS were higher than negative controls and lower than celiac disease (18.5 ± 6.4, 11.9 ± 2.8, and 40.8 ± 8.1 IELs/100 enterocytes; p<0.001). CD4 were lower in NCGS than controls and celiac disease (31.0 ± 22.1, 72.5 ± 29.5, and 103.7 ± 15.7 cells/mm2; p<0.001). CD8 in NCGS were similar to negative controls, but lower than celiac disease (14.0 ± 7.4 and 34.0 ± 7.1 IELs/100 enterocytes, p<0.001). CD117 were higher in NCGS than celiac disease and negative controls (145.8 ± 49.9, 121.3 ± 13.1, and 113.5 ± 23.4 cells/mm2; p=0.009). Conclusions. The combination of CD4 and CD117, as well as IEL characterization, may be useful to support a clinical diagnosis of NCGS.
6

Kisielow, Jan, Luigi Tortola, Jacqueline Weber, Klaus Karjalainen та Manfred Kopf. "Evidence for the divergence of innate and adaptive T-cell precursors before commitment to the αβ and γδ lineages". Blood 118, № 25 (15 грудня 2011): 6591–600. http://dx.doi.org/10.1182/blood-2011-05-352732.

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Abstract In addition to adaptive T cells, the thymus supports the development of unconventional T cells such as natural killer T (NKT) and CD8αα intraepithelial lymphocytes (IELs), which have innate functional properties, particular antigenic specificities, and tissue localization. Both conventional and innate T cells are believed to develop from common precursors undergoing instructive, TCR-mediated lineage fate decisions, but innate T cells are proposed to undergo positive instead of negative selection in response to agonistic TCR signals. In the present study, we show that, in contrast to conventional αβT cells, innate αβT cells are not selected against functional TCRγ rearrangements and express TCRγ mRNA. Likewise, in contrast to the majority of γδT cells, thymic innate γδT cells are not efficiently selected against functional TCRβ chains. In precursors of conventional T cells, autonomous TCR signals emanating from the pre-TCR or γδTCR in the absence of ligand mediate selection against the TCR of the opposite isotype and αβ/γδ lineage commitment. Our data suggest that developing innate T cells ignore such signals and rely solely on agonistic TCR interactions. Consistently, most innate T cells reacted strongly against autologous thymocytes. These results suggest that innate and adaptive T-cell lineages do not develop from the same pool of precursors and potentially diverge before αβ/γδ lineage commitment.
7

Billiet, Lore, Glenn Goetgeluk, Sarah Bonte, Stijn De Munter, Laurenz De Cock, Melissa Pille, Joline Ingels, et al. "Human Thymic CD10+ PD-1+ Intraepithelial Lymphocyte Precursors Acquire Interleukin-15 Responsiveness at the CD1a– CD95+ CD28– CCR7– Developmental Stage." International Journal of Molecular Sciences 21, no. 22 (November 20, 2020): 8785. http://dx.doi.org/10.3390/ijms21228785.

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Human thymic CD8αα+ CD10+ PD-1+ αβ T cells selected through early agonist selection have been proposed as the putative thymic precursors of the human CD8αα+ intestinal intraepithelial lymphocytes (IELs). However, the progeny of these thymic precursor cells in human blood or tissues has not yet been characterized. Here, we studied the phenotypical and transcriptional differentiation of the thymic IEL precursor (IELp) lineage upon in vitro exposure to cytokines prominent in the peripheral tissues such as interleukin-15 (IL-15) and the inflammatory cytokines interleukin-12 (IL-12) and interleukin-18 (IL-18). We showed that only the CD1a− fraction of the CD10+ PD-1+ IELp population was able to proliferate with IL-15, suggesting that this subset had acquired functionality. These cells downregulated PD-1 expression and completely lost CD10 expression, whereas other surface markers such as CD95 and CXCR3 remained highly expressed. RNA-seq analysis of the IL-15-cultured cells clearly showed induction of innate-like and effector genes. Induction of the cytotoxic machinery by the CD10+ PD-1+ population was acquired in the presence of IL-15 and was further augmented by inflammatory cytokines. Our data suggest that only the CD1a− CD10+ PD-1+ population exits the thymus and survives in the periphery. Furthermore, PD-1 and CD10 expression is not an intrinsic property of this lineage, but rather characterizes a transient stage in differentiation. CD95 and CXCR3 expression combined with the absence of CD28, CCR7, and CD6 expression might be more powerful markers to define this lineage in the periphery.
8

Clarizio, A. V., H. J. Galipeau, J. Jury, L. Rondeau, J. Godbout, L. Williams, B. Anderson, and E. Verdu. "A19 NOVEL HLA-DQ2 TRANSGENIC MICE DEVELOP GLUTEN-IMMUNOPATHOLOGY FOLLOWING GLUTEN SENSITIZATION." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (February 2020): 22–23. http://dx.doi.org/10.1093/jcag/gwz047.018.

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Abstract Background Celiac disease (CeD), an autoimmune and chronic inflammatory enteropathy triggered by the ingestion of gluten, is associated with HLA-DQ2 (~90%) and, to a lesser extent, HLA-DQ8. We previously characterized a humanized mouse model of gluten sensitivity that expresses the HLA-DQ8 allele, and that develops mild innate and adaptive immune pathways related to DQ8+ CeD patients. Gluten peptides recognized in the context of DQ2 differ from those bound to DQ8 molecules and homozygous carriage of HLA-DQ2 provides higher risk for CeD development. Thus, characterization of a transgenic HLA-DQ2 model would allow for the investigation of disease pathways that affect the majority of celiac patients. Aims Our aim was to determine gluten-immune responses and small intestinal pathology in C57BL/6 mice humanized with the HLA DR3-DQ2 gene. Methods To break oral tolerance to gluten, DR3-DQ2 mice were orally sensitized with gliadin (5mg/mL) and cholera toxin (CT; 2.5mg/mL) before being challenged with gluten (10mg/mL) for three weeks. Non-sensitized DR3-DQ2 controls mice received CT and a sham challenge. To determine the effects of long-term exposure to gluten, gliadin sensitized DR3-DQ2 mice were placed on a gluten-containing diet for twelve weeks. Controls were given CT and remained on a gluten-free diet. Pathology was evaluated by CD3+ intraepithelial lymphocytes (IELs) counts; villus-crypt (V/C) ratios. Gluten-induced immune responses were evaluated by anti-tissue transglutaminase-2 (tTG) and anti-gliadin antibodies, inflammatory gene expression by Nanostring Technology, and CD4+ T cell proliferation using flow cytometry. Intestinal permeability was measured in vitro by Ussing Chamber. Results DR3-DQ2 mice that were sensitized and challenged with gluten for three weeks had higher IEL counts, lower V/C ratios, higher anti-gliadin and tTG antibodies, which are used in the serological diagnosis of the disease. Gluten sensitized mice also has higher expression of pro-inflammatory genes, and an induction of gluten specific T cells, but no changes in permeability compared to control mice. DR3-DQ2 mice given a gluten-containing diet for 12 weeks also had higher IEL counts, lower V/C ratios, and higher anti-gliadin and tTG antibodies, but had no changes in permeability compared to controls. Conclusions These results indicate that mice humanized with the HLA DR3-DQ2 gene show innate and gluten-specific immune responses following sensitization. Thus, mice expressing HLA-DQ2 represents a novel model of gluten sensitivity that can be used to investigate celiac disease pathways related to gluten peptide repertoire that binds to DQ2 MHC class II, encoded by the HLA gene expressed by the majority of celiac patients. Supported by CIHR to EFV and OGS to AVC Funding Agencies CIHROGS
9

Bhinder, Ganive, Martin Stahl, Ho Pan Sham, Shauna M. Crowley, Vijay Morampudi, Udit Dalwadi, Caixia Ma, Kevan Jacobson, and Bruce A. Vallance. "Intestinal Epithelium-Specific MyD88 Signaling Impacts Host Susceptibility to Infectious Colitis by Promoting Protective Goblet Cell and Antimicrobial Responses." Infection and Immunity 82, no. 9 (June 23, 2014): 3753–63. http://dx.doi.org/10.1128/iai.02045-14.

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ABSTRACTIntestinal epithelial cells (IECs), including secretory goblet cells, form essential physiochemical barriers that separate luminal bacteria from underlying immune cells in the intestinal mucosa. IECs are common targets for enteric bacterial pathogens, with hosts responding to these microbes through innate toll-like receptors that predominantly signal through the MyD88 adaptor protein. In fact, MyD88 signaling confers protection against several enteric bacterial pathogens, includingSalmonella entericaserovar Typhimurium andCitrobacter rodentium. Since IECs are considered innately hyporesponsive, it is unclear whether MyD88 signaling within IECs contributes to this protection. We infected mice lacking MyD88 solely in their IECs (IEC-Myd88−/−) withS.Typhimurium. Compared to wild-type (WT) mice, infectedIEC-Myd88−/−mice suffered accelerated tissue damage, exaggerated barrier disruption, and impaired goblet cell responses (Muc2 and RELMβ). Immunostaining revealedS.Typhimurium penetrated the IECs ofIEC-Myd88−/−mice, unlike in WT mice, where they were sequestered to the lumen. When isolated crypts were assayed for their antimicrobial actions, crypts fromIEC-Myd88−/−mice were severely impaired in their antimicrobial activity againstS.Typhimurium. We also examined whether MyD88 signaling in IECs impacted host defense againstC. rodentium, withIEC-Myd88−/−mice again suffering exaggerated tissue damage, impaired goblet cell responses, and reduced antimicrobial activity againstC. rodentium. These results demonstrate that MyD88 signaling within IECs plays an important protective role at early stages of infection, influencing host susceptibility to infection by controlling the ability of the pathogen to reach and survive at the intestinal mucosal surface.
10

Hosomi, Shuhei, Joep Grootjans, Markus Tschurtschenthaler, Niklas Krupka, Juan D. Matute, Magdalena B. Flak, Eduardo Martinez-Naves, et al. "Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation." Journal of Experimental Medicine 214, no. 10 (July 26, 2017): 2985–97. http://dx.doi.org/10.1084/jem.20162041.

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Endoplasmic reticulum (ER) stress is commonly observed in intestinal epithelial cells (IECs) and can, if excessive, cause spontaneous intestinal inflammation as shown by mice with IEC-specific deletion of X-box–binding protein 1 (Xbp1), an unfolded protein response–related transcription factor. In this study, Xbp1 deletion in the epithelium (Xbp1ΔIEC) is shown to cause increased expression of natural killer group 2 member D (NKG2D) ligand (NKG2DL) mouse UL16-binding protein (ULBP)–like transcript 1 and its human orthologue cytomegalovirus ULBP via ER stress–related transcription factor C/EBP homology protein. Increased NKG2DL expression on mouse IECs is associated with increased numbers of intraepithelial NKG2D-expressing group 1 innate lymphoid cells (ILCs; NK cells or ILC1). Blockade of NKG2D suppresses cytolysis against ER-stressed epithelial cells in vitro and spontaneous enteritis in vivo. Pharmacological depletion of NK1.1+ cells also significantly improved enteritis, whereas enteritis was not ameliorated in Recombinase activating gene 1−/−;Xbp1ΔIEC mice. These experiments reveal innate immune sensing of ER stress in IECs as an important mechanism of intestinal inflammation.
11

Charania, Moiz A., Hamed Laroui, Hongchun Liu, Emilie Viennois, Saravanan Ayyadurai, Bo Xiao, Sarah A. Ingersoll, Daniel Kalman, and Didier Merlin. "Intestinal Epithelial CD98 Directly Modulates the Innate Host Response to Enteric Bacterial Pathogens." Infection and Immunity 81, no. 3 (January 7, 2013): 923–34. http://dx.doi.org/10.1128/iai.01388-12.

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ABSTRACTCD98 is a type II transmembrane glycoprotein whose expression increases in intestinal epithelial cells (IECs) during intestinal inflammation. EnteropathogenicEscherichia coli(EPEC) is a food-borne human pathogen that attaches to IECs and injects effector proteins directly into the host cells, thus provoking an inflammatory response. In the present study, we investigated CD98 and EPEC interactionsin vitroandex vivoand examined FVB wild-type (WT) and villin-CD98 transgenic mice overexpressing human CD98 in IECs (hCD98 Tg mice) and infected withCitrobacter rodentiumas anin vivomodel.In vivostudies indicated that CD98 overexpression, localized to the apical domain of colonic cells, increased the attachment ofC. rodentiumin mouse colons and resulted in increased expression of proinflammatory markers and decreased expression of anti-inflammatory markers. The proliferative markers Ki-67 and cyclin D1 were significantly increased in the colonic tissue ofC. rodentium-infected hCD98 Tg mice compared to that of WT mice.Ex vivostudies correlate with thein vivodata. Small interfering RNA (siRNA) studies with Caco2-BBE cells showed a decrease in adherence of EPEC to Caco2 cells in which CD98 expression was knocked down.In vitrosurface plasmon resonance (SPR) experiments showed direct binding between recombinant hCD98 and EPEC/C. rodentiumproteins. We also demonstrated that the partial extracellular loop of hCD98 was sufficient for direct binding to EPEC/C. rodentium. These findings demonstrate the importance of the extracellular loop of CD98 in the innate host defense response to intestinal infection by attaching and effacing (A/E) pathogens.
12

Bogunovic, Milena, Shaival H. Davé, Jeremy S. Tilstra, Diane T. W. Chang, Noam Harpaz, Huabao Xiong, Lloyd F. Mayer, and Scott E. Plevy. "Enteroendocrine cells express functional Toll-like receptors." American Journal of Physiology-Gastrointestinal and Liver Physiology 292, no. 6 (June 2007): G1770—G1783. http://dx.doi.org/10.1152/ajpgi.00249.2006.

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Intestinal epithelial cells (IECs) provide a physical and immunological barrier against enteric microbial flora. Toll-like receptors (TLRs), through interactions with conserved microbial patterns, activate inflammatory gene expression in cells of the innate immune system. Previous studies of the expression and function of TLRs in IECs have reported varying results. Therefore, TLR expression was characterized in human and murine intestinal sections, and TLR function was tested in an IEC line. TLR1, TLR2, and TLR4 are coexpressed on a subpopulation of human and murine IECs that reside predominantly in the intestinal crypt and belong to the enteroendocrine lineage. An enteroendocrine cell (EEC) line demonstrated a similar expression pattern of TLRs as primary cells. The murine EEC line STC-1 was activated with specific TLR ligands: LPS or synthetic bacterial lipoprotein. In STC-1 cells stimulated with bacterial ligands, NF-κB and MAPK activation was demonstrated. Furthermore, the expression of TNF and macrophage inhibitory protein-2 were induced. Additionally, bacterial ligands induced the expression of the anti-inflammatory gene transforming growth factor-β. LPS triggered a calcium flux in STC-1 cells, resulting in a rapid increase in CCK secretion. Finally, conditioned media from STC-1 cells inhibited the production of nitric oxide and IL-12 p40 by activated macrophages. In conclusion, human and murine IECs that express TLRs belong to the enteroendocrine lineage. Using a murine EEC model, a broad range of functional effects of TLR activation was demonstrated. This study suggests a potential role for EECs in innate immune responses.
13

Lotz, Michael, Dominique Gütle, Sabrina Walther, Sandrine Ménard, Christian Bogdan, and Mathias W. Hornef. "Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells." Journal of Experimental Medicine 203, no. 4 (April 10, 2006): 973–84. http://dx.doi.org/10.1084/jem.20050625.

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The role of innate immune recognition by intestinal epithelial cells (IECs) in vivo is ill-defined. Here, we used highly enriched primary IECs to analyze Toll-like receptor (TLR) signaling and mechanisms that prevent inappropriate stimulation by the colonizing microflora. Although the lipopolysaccharide (LPS) receptor complex TLR4/MD-2 was present in fetal, neonatal, and adult IECs, LPS-induced nuclear factor κB (NF-κB) activation and chemokine (macrophage inflammatory protein 2 [MIP-2]) secretion was only detected in fetal IECs. Fetal intestinal macrophages, in contrast, were constitutively nonresponsive to LPS. Acquisition of LPS resistance was paralleled by a spontaneous activation of IECs shortly after birth as illustrated by phosphorylation of IκB-α and nuclear translocation of NF-κB p65 in situ as well as transcriptional activation of MIP-2. Importantly, the spontaneous IEC activation occurred in vaginally born mice but not in neonates delivered by Caesarean section or in TLR4-deficient mice, which together with local endotoxin measurements identified LPS as stimulatory agent. The postnatal loss of LPS responsiveness of IECs was associated with a posttranscriptional down-regulation of the interleukin 1 receptor–associated kinase 1, which was essential for epithelial TLR4 signaling in vitro. Thus, unlike intestinal macrophages, IECs acquire TLR tolerance immediately after birth by exposure to exogenous endotoxin to facilitate microbial colonization and the development of a stable intestinal host–microbe homeostasis.
14

Li, Tianming, Mei Liu, Siyu Sun, Xuying Liu, and Dongyan Liu. "Epithelial Cells Orchestrate the Functions of Dendritic Cells in Intestinal Homeostasis." Journal of Biomedical Research & Environmental Sciences 1, no. 7 (November 2020): 343–52. http://dx.doi.org/10.37871/jbres1165.

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The gastrointestinal tract represents the largest mucosal membrane surface and is the one of the most complex human organs. The intestinal barrier dysfunction contributes to systemic immune activation. The mucosal immune system has extremely arduous tasks to resist invaders and promote tolerance of food antigens and the microbiota. The intestinal mucosal immune system fulfills these tasks through complex interactions between immune cells and the local microenvironment in intestine. Intestinal Epithelial Cells (IECs) play important roles in these complex interactions. IECs not only constitute the first barrier of the intestine but also are crucial for integrating external and internal signals and for coordinating the ensuing immune response. Dendritic Cells (DCs) play key roles in shaping the intestinal immune response by their ability to coordinate protective immunity and immune tolerance in the host. DCs are pivotal actors in the connection between innate and adaptive immune responses. The IECs coordinate with the DCs in immune recognition, tolerance and host defense mechanisms. In this review, we will summarize how IECs orchestrate intestinal DCs in intestinal homeostasis and diseases.
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Negroni, Anna, Salvatore Cucchiara, and Laura Stronati. "Apoptosis, Necrosis, and Necroptosis in the Gut and Intestinal Homeostasis." Mediators of Inflammation 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/250762.

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Intestinal epithelial cells (IECs) form a physiochemical barrier that separates the intestinal lumen from the host’s internal milieu and is critical for electrolyte passage, nutrient absorption, and interaction with commensal microbiota. Moreover, IECs are strongly involved in the intestinal mucosal inflammatory response as well as in mucosal innate and adaptive immune responses. Cell death in the intestinal barrier is finely controlled, since alterations may lead to severe disorders, including inflammatory diseases. The emerging picture indicates that intestinal epithelial cell death is strictly related to the maintenance of tissue homeostasis. This review is focused on previous reports on different forms of cell death in intestinal epithelium.
16

Cao, Qi, Shayla M. McIsaac, and Andrew W. Stadnyk. "Human colonic epithelial cells detect and respond to C5a via apically expressed C5aR through the ERK pathway." American Journal of Physiology-Cell Physiology 302, no. 12 (June 15, 2012): C1731—C1740. http://dx.doi.org/10.1152/ajpcell.00213.2011.

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Intestinal epithelial cells (IECs) exhibit numerous adaptations to maintain barrier function as well as play sentinel roles by expressing receptors for microbial products and antimicrobial peptides. The complement system is another important innate sensing and defense mechanism of the host against bacteria and increasing evidence shows that complement plays a role in colitis. The split component C5a is a potent proinflammatory molecule, and the C5a receptor (C5aR) CD88 has been reported on multiple cell types. Here, we examined the question of whether human colonic cell lines can detect activated complement via C5aR and what signaling pathway is critical in the subsequent responses. T84, HT29, and Caco2 cell lines all possessed mRNA and protein for C5aR and the decoy receptor C5L2. Polarized cells expressed the proteins on the apical cell membrane. C5a binding to the C5aR on human IECs activates the ERK pathway, which proved critical for a subsequent upregulation of IL-8 mRNA, increased permeability of monolayers, and enhanced proliferation of the cells. The fact that human IECs are capable of detecting complement activation in the lumen via this anaphylatoxin receptor highlights the potential for IECs to detect pathogens indirectly through complement activation and be primed to amplify the host response through heightened inflammatory mediator expression to further recruit immune cells.
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Zhou, Rongbin, Haiming Wei, Rui Sun, Jian Zhang, and Zhigang Tian. "NKG2D recognition mediates Toll-like receptor 3 signaling-induced breakdown of epithelial homeostasis in the small intestines of mice." Proceedings of the National Academy of Sciences 104, no. 18 (April 26, 2007): 7512–15. http://dx.doi.org/10.1073/pnas.0700822104.

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Toll-like receptors (TLRs) and NK receptors are the two most important receptor families in innate immunity. Although it has been observed that TLR signaling can induce or up-regulate the expression of the ligands for stimulatory NK receptors on monocytes or muscle cells, there is not yet a report indicating whether TLR signaling can break down self-tolerance through NK receptors. The present work reports that TLR3 signaling by polyinosinic–polycytidylic acid stimulation induces intestinal epithelial cells (IECs) to express retinoic acid early inducible-1 (a ligand for NKG2D) and to induce NKG2D expression on CD8αα intestinal intraepithelial lymphocytes by IL-15 derived from TLR3-activated IECs. The blockade of interaction between NKG2D and Rae1 inhibits the cytotoxicity of intraepithelial lymphocytes against IECs in a cell–cell contact-dependent manner and therefore alleviates polyinosinic–polycytidylic acid-induced epithelial destruction and acute mucosal injury of small intestine. These results demonstrate that TLR signaling induces tissue injury through the NKG2D pathway, suggesting that TLR signaling may break down self-tolerance through induction of abnormal expression of ligands for stimulatory NK receptors.
18

Zhang, Wei, Jiang-Yuan Du, Qing Yu, and Jun-O. Jin. "Interleukin-7 Produced by Intestinal Epithelial Cells in Response to Citrobacter rodentium Infection Plays a Major Role in Innate Immunity against This Pathogen." Infection and Immunity 83, no. 8 (June 1, 2015): 3213–23. http://dx.doi.org/10.1128/iai.00320-15.

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Interleukin-7 (IL-7) engages multiple mechanisms to overcome chronic viral infections, but the role of IL-7 in bacterial infections, especially enteric bacterial infections, remains unclear. Here we characterized the previously unexplored role of IL-7 in the innate immune response to the attaching and effacing bacteriumCitrobacter rodentium.C. rodentiuminfection induced IL-7 production from intestinal epithelial cells (IECs). IL-7 production from IECs in response toC. rodentiumwas dependent on gamma interferon (IFN-γ)-producing NK1.1+cells and IL-12. Treatment with anti-IL-7Rα antibody duringC. rodentiuminfection resulted in a higher bacterial burden, enhanced intestinal damage, and greater weight loss and mortality than observed with the control IgG treatment. IEC-produced IL-7 was only essential for protective immunity againstC. rodentiumduring the first 6 days after infection. An impaired bacterial clearance upon IL-7Rα blockade was associated with a significant decrease in macrophage accumulation and activation in the colon. Moreover,C. rodentium-induced expansion and activation of intestinal CD4+lymphoid tissue inducer (LTi) cells was completely abrogated by IL-7Rα blockade. Collectively, these data demonstrate that IL-7 is produced by IECs in response toC. rodentiuminfection and plays a critical role in the protective immunity against this intestinal attaching and effacing bacterium.
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Lemme-Dumit, J. M., M. A. Polti, G. Perdigón, and C. Maldonado Galdeano. "Probiotic bacteria cell walls stimulate the activity of the intestinal epithelial cells and macrophage functionality." Beneficial Microbes 9, no. 1 (January 29, 2018): 153–64. http://dx.doi.org/10.3920/bm2016.0220.

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The effect of oral administration of probiotic bacteria cell walls (PBCWs) in the stimulation of the immune system in healthy BALB/c mice was evaluated. We focused our investigation mainly on intestinal epithelial cells (IECs) which are essential for coordinating an adequate mucosal immune response and on the functionality of macrophages. The probiotic bacteria and their cell walls were able to stimulate the IECs exhibiting an important activation and cytokine releases. Supplementation with PBCWs promoted macrophage activation from peritoneum and spleen, indicating that the PBCWs oral administration was able to improve the functionality of the macrophages. In addition, the PBCWs increased immunoglobulin A (IgA)-producing cells in the gut lamina propria in a similar way to probiotic bacteria, but this supplementation did not have an effect on the population of goblet cells in the small intestine epithelium. These results indicate that the probiotic bacteria and their cell walls have an important immunoregulatory effect on the IECs without altering the homeostatic environment but with an increase in IgA+ producing cells and in the innate immune cells, mainly those distant from the gut such as spleen and peritoneum. These findings about the capacity of the cell walls from probiotic bacteria to stimulate key cells, such as IECs and macrophages, and to improve the functioning of the immune system, suggest that those structures could be applied as a new oral adjuvant.
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Woida, Patrick J., and Karla J. F. Satchell. "The Vibrio cholerae MARTX toxin silences the inflammatory response to cytoskeletal damage before inducing actin cytoskeleton collapse." Science Signaling 13, no. 614 (January 14, 2020): eaaw9447. http://dx.doi.org/10.1126/scisignal.aaw9447.

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Multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are pore-forming bacterial toxins that translocate multiple functionally independent effector domains into a target eukaryotic cell. Vibrio cholerae colonizes intestinal epithelial cells (IECs) and uses a MARTX toxin with three effector domains—an actin cross-linking domain (ACD), a Rho inactivation domain (RID), and an α/β hydrolase domain (ABH)—to suppress innate immunity and enhance colonization. We investigated whether these multiple catalytic enzymes delivered from a single toxin functioned in a coordinated manner to suppress intestinal innate immunity. Using cultured human IECs, we demonstrated that ACD-induced cytoskeletal collapse activated extracellular signal–regulated kinase, p38, and c-Jun amino-terminal kinase mitogen-activated protein kinase (MAPK) signaling to elicit a robust proinflammatory response characterized by the secretion of interleukin-8 (IL-8; also called CXCL8) and the expression of CXCL8, tumor necrosis factor (TNF), and other proinflammatory genes. However, RID and ABH, which are naturally delivered together with ACD, blocked MAPK activation through Rac1 and thus prevented ACD-induced inflammation. RID also abolished IL-8 secretion induced by heat-killed bacteria, TNF, or latrunculin A. Thus, MARTX toxins use enzymatic multifunctionality to silence the host response to bacterial factors and to the damage caused by the toxins. Furthermore, these data show how V. cholerae MARTX toxin suppresses intestinal inflammation and contributes to cholera being classically defined as a noninflammatory diarrheal disease.
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Mills, Dominic C., Ozan Gundogdu, Abdi Elmi, Mona Bajaj-Elliott, Peter W. Taylor, Brendan W. Wren, and Nick Dorrell. "Increase in Campylobacter jejuni Invasion of Intestinal Epithelial Cells under Low-Oxygen Coculture Conditions That Reflect theIn VivoEnvironment." Infection and Immunity 80, no. 5 (February 21, 2012): 1690–98. http://dx.doi.org/10.1128/iai.06176-11.

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ABSTRACTCampylobacter jejuniinfection often results in bloody, inflammatory diarrhea, indicating bacterial disruption and invasion of the intestinal epithelium. WhileC. jejuniinfection can be reproducedin vitrousing intestinal epithelial cell (IEC) lines, low numbers of bacteria invading IECs do not reflect these clinical symptoms. Performingin vitroassays under atmospheric oxygen conditions neither is optimal for microaerophilicC. jejuninor reflects the low-oxygen environment of the intestinal lumen. A vertical diffusion chamber (VDC) model system creates microaerobic conditions at the apical surface and aerobic conditions at the basolateral surface of cultured IECs, producing anin vitrosystem that closely mimicsin vivoconditions in the human intestine. Ninefold increases in interacting and 80-fold increases in intracellularC. jejuni11168H wild-type strain bacteria were observed after 24-h coculture with Caco-2 IECs in VDCs under microaerobic conditions at the apical surface, compared to results under aerobic conditions. Increased bacterial interaction was matched by an enhanced and directional host innate immune response, particularly an increased basolateral secretion of the proinflammatory chemokine interleukin-8 (IL-8). Analysis of the invasive ability of a nonmotileC. jejuni11168HrpoNmutant in the VDC model system indicates that motility is an important factor in the early stages of bacterial invasion. The first report of the use of a VDC model system for studying the interactions of an invasive bacterial pathogen with IECs demonstrates the importance of performing such experiments under conditions that represent thein vivosituation and will allow novel insights intoC. jejunipathogenic mechanisms.
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Chen, Jie, Jaladanki N. Rao, Tongtong Zou, Lan Liu, Bernard S. Marasa, Lan Xiao, Xing Zeng, Douglas J. Turner, and Jian-Ying Wang. "Polyamines are required for expression of Toll-like receptor 2 modulating intestinal epithelial barrier integrity." American Journal of Physiology-Gastrointestinal and Liver Physiology 293, no. 3 (September 2007): G568—G576. http://dx.doi.org/10.1152/ajpgi.00201.2007.

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The Toll-like receptors (TLRs) allow mammalian intestinal epithelium to detect various microbes and activate innate immunity after infection. TLR2 and TLR4 have been identified in intestinal epithelial cells (IECs) as fundamental components of the innate immune response to bacterial pathogens, but the exact mechanism involved in control of TLR expression remains unclear. Polyamines are implicated in a wide variety of biological functions, and regulation of cellular polyamines is a central convergence point for the multiple signaling pathways driving different epithelial cell functions. The current study determined whether polyamines regulate TLR expression, thereby modulating intestinal epithelial barrier function. Depletion of cellular polyamines by inhibiting ornithine decarboxylase (ODC) with α-difluoromethylornithine decreased levels of TLR2 mRNA and protein, whereas increased polyamines by ectopic overexpression of the ODC gene enhanced TLR2 expression. Neither intervention changed basal levels of TLR4. Exposure of normal IECs to low-dose (5 μg/ml) LPS increased ODC enzyme activity and stimulated expression of TLR2 but not TLR4, while polyamine depletion prevented this LPS-induced TLR2 expression. Decreased TLR2 in polyamine-deficient cells was associated with epithelial barrier dysfunction. In contrast, increased TLR2 by the low dose of LPS enhanced epithelial barrier function, which was abolished by inhibition of TLR2 expression with specific, small interfering RNA. These results indicate that polyamines are necessary for TLR2 expression and that polyamine-induced TLR2 activation plays an important role in regulating epithelial barrier function.
23

Stone, Virginia M., Emma E. Ringqvist, Pär G. Larsson, Erna Domsgen, Ulrika Holmlund, Eva Sverremark-Ekström, and Malin Flodström-Tullberg. "Inhibition of Type III Interferon Expression in Intestinal Epithelial Cells—A Strategy Used by Coxsackie B Virus to Evade the Host’s Innate Immune Response at the Primary Site of Infection?" Microorganisms 9, no. 1 (January 5, 2021): 105. http://dx.doi.org/10.3390/microorganisms9010105.

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Increasing evidence highlights the importance of the antiviral activities of the type III interferons (IFNλs; IL-28A, IL-28B, IL29, and IFNλ4) in the intestine. However, many viruses have developed strategies to counteract these defense mechanisms by preventing the production of IFNs. Here we use infection models, a clinical virus isolate, and several molecular biology techniques to demonstrate that both type I and III IFNs induce an antiviral state and attenuate Coxsackievirus group B (CVB) replication in human intestinal epithelial cells (IECs). While treatment of IECs with a viral mimic (poly (I:C)) induced a robust expression of both type I and III IFNs, no such up-regulation was observed after CVB infection. The blunted IFN response was paralleled by a reduction in the abundance of proteins involved in the induction of interferon gene transcription, including TIR-domain-containing adapter-inducing interferon-β (TRIF), mitochondrial antiviral-signaling protein (MAVS), and the global protein translation initiator eukaryotic translation initiation factor 4G (eIF4G). Taken together, this study highlights a potent anti-Coxsackieviral effect of both type I and III IFNs in cells located at the primary site of infection. Furthermore, we show for the first time that the production of type I and III IFNs in IECs is blocked by CVBs. These findings suggest that CVBs evade the host immune response in order to successfully infect the intestine.
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Giacomin, Paul R., Ryan H. Moy, Mario Noti, Lisa C. Osborne, Mark C. Siracusa, Theresa Alenghat, Bigang Liu та ін. "Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity". Journal of Experimental Medicine 212, № 10 (14 вересня 2015): 1513–28. http://dx.doi.org/10.1084/jem.20141831.

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Innate lymphoid cells (ILCs) are critical for maintaining epithelial barrier integrity at mucosal surfaces; however, the tissue-specific factors that regulate ILC responses remain poorly characterized. Using mice with intestinal epithelial cell (IEC)–specific deletions in either inhibitor of κB kinase (IKK)α or IKKβ, two critical regulators of NFκB activation, we demonstrate that IEC-intrinsic IKKα expression selectively regulates group 3 ILC (ILC3)–dependent antibacterial immunity in the intestine. Although IKKβΔIEC mice efficiently controlled Citrobacter rodentium infection, IKKαΔIEC mice exhibited severe intestinal inflammation, increased bacterial dissemination to peripheral organs, and increased host mortality. Consistent with weakened innate immunity to C. rodentium, IKKαΔIEC mice displayed impaired IL-22 production by RORγt+ ILC3s, and therapeutic delivery of rIL-22 or transfer of sort-purified IL-22–competent ILCs from control mice could protect IKKαΔIEC mice from C. rodentium–induced morbidity. Defective ILC3 responses in IKKαΔIEC mice were associated with overproduction of thymic stromal lymphopoietin (TSLP) by IECs, which negatively regulated IL-22 production by ILC3s and impaired innate immunity to C. rodentium. IEC-intrinsic IKKα expression was similarly critical for regulation of intestinal inflammation after chemically induced intestinal damage and colitis. Collectively, these data identify a previously unrecognized role for epithelial cell–intrinsic IKKα expression and TSLP in regulating ILC3 responses required to maintain intestinal barrier immunity.
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Østvik, Ann Elisabet, Tarjei Dahl Svendsen, Atle van Beelen Granlund, Berit Doseth, Helene Kolstad Skovdahl, Ingunn Bakke, Silje Thorsvik, et al. "Intestinal Epithelial Cells Express Immunomodulatory ISG15 During Active Ulcerative Colitis and Crohn’s Disease." Journal of Crohn's and Colitis 14, no. 7 (February 5, 2020): 920–34. http://dx.doi.org/10.1093/ecco-jcc/jjaa022.

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Abstract Background and Aims Intestinal epithelial cells [IECs] secrete cytokines that recruit immune cells to the mucosa and regulate immune responses that drive inflammation in inflammatory bowel disease [IBD]. However, experiments in patient-derived IEC models are still scarce. Here, we aimed to investigate how innate immunity and IEC-specific pattern recognition receptor [PRR] signalling can be involved in an enhanced type I interferon [IFN] gene signature observed in colon epithelium of patients with active IBD, with a special focus on secreted ubiquitin-like protein ISG15. Methods Gene and protein expression in whole mucosa biopsies and in microdissected human colonic epithelial lining, in HT29 human intestinal epithelial cells and primary 3D colonoids treated with PRR-ligands and cytokines, were detected by transcriptomics, in situ hybridisation, immunohistochemistry, western blots, and enzyme-linked immunosorbent assay [ELISA]. Effects of IEC-secreted cytokines were examined in human peripheral blood mononuclear cells [PBMCs] by multiplex chemokine profiling and ELISA. Results The type I IFN gene signature in human mucosal biopsies was mimicked in Toll-like receptor TLR3 and to some extent tumour necrosis factor [TNF]-treated human IECs. In intestinal biopsies, ISG15 expression correlated with expression of the newly identified receptor for extracellular ISG15, LFA-1 integrin. ISG15 was expressed and secreted from HT29 cells and primary 3D colonoids through both JAK1-pSTAT-IRF9-dependent and independent pathways. In experiments using PBMCs, we show that ISG15 releases IBD-relevant proinflammatory cytokines such as CXCL1, CXCL5, CXCL8, CCL20, IL1, IL6, TNF, and IFNγ. Conclusions ISG15 is secreted from primary IECs upon extracellular stimulation, and mucosal ISG15 emerges as an intriguing candidate for immunotherapy in IBD.
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Rees, William D., Martin Stahl, Kevan Jacobson, Brian Bressler, Laura M. Sly, Bruce A. Vallance, and Theodore S. Steiner. "Enteroids Derived From Inflammatory Bowel Disease Patients Display Dysregulated Endoplasmic Reticulum Stress Pathways, Leading to Differential Inflammatory Responses and Dendritic Cell Maturation." Journal of Crohn's and Colitis 14, no. 7 (December 4, 2019): 948–61. http://dx.doi.org/10.1093/ecco-jcc/jjz194.

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Abstract Background and Aims Endoplasmic reticulum [ER] stress in intestinal epithelial cells [IECs] contributes to the pathogenesis of inflammatory bowel disease [IBD]. We hypothesized that ER stress changes innate signalling in human IECs, augmenting toll-like receptor [TLR] responses and inducing pro-inflammatory changes in underlying dendritic cells [DCs]. Methods Caco-2 cells and primary human colon-derived enteroid monolayers were exposed to ATP [control stressor] or thapsigargin [Tg] [ER stress inducer], and were stimulated with the TLR5 agonist flagellin. Cytokine release was measured by an enzyme immunoassay. ER stress markers CHOP, GRP78 and XBP1s/u were measured via quantitative PCR and Western blot. Monocyte-derived DCs [moDCs] were cultured with the IEC supernatants and their activation state was measured. Responses from enteroids derived from IBD patients and healthy control participants were compared. Results ER stress enhanced flagellin-induced IL-8 release from Caco-2 cells and enteroids. Moreover, conditioned media activated DCs to become pro-inflammatory, with increased expression of CD80, CD86, MHCII, IL-6, IL-15 and IL-12p70 and decreased expression of CD103 and IL-10. Flagellin-induced IL-8 production correlated with DC activation, suggesting a common stress pathway. Moreover, there were distinct differences in cytokine expression and basal ER stress between IBD and healthy subject-derived enteroid monolayers, suggesting a dysregulated ER stress pathway in IBD-derived enteroids. Conclusions Cellular stress enhances TLR5 responses in IECs, leading to increased DC activation, indicating a previously unknown mechanistic link between epithelial ER stress and immune activation in IBD. Furthermore, dysregulated ER stress may be propagated from the intestinal epithelial stem cell niche in IBD patients.
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Guma, Monica, Dariusz Stepniak, Helena Shaked, Martina E. Spehlmann, Steve Shenouda, Hilde Cheroutre, Ildelfonso Vicente-Suarez, Lars Eckmann, Martin F. Kagnoff та Michael Karin. "Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation". Journal of Experimental Medicine 208, № 9 (8 серпня 2011): 1889–900. http://dx.doi.org/10.1084/jem.20110242.

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Nuclear factor (NF)-κB, activated by IκB kinase (IKK), is a key regulator of inflammation, innate immunity, and tissue integrity. NF-κB and one of its main activators and transcriptional targets, tumor necrosis factor (TNF), are up-regulated in many inflammatory diseases that are accompanied by tissue destruction. The etiology of many inflammatory diseases is poorly understood, but often depends on genetic factors and environmental triggers that affect NF-κB and related pathways. It is unknown, however, whether persistent NF-κB activation is sufficient for driving symptomatic chronic inflammation and tissue damage. To address this question, we generated IKKβ(EE)IEC mice, which express a constitutively active form of IKKβ in intestinal epithelial cell (IECs). IKKβ(EE)IEC mice exhibit NF-κB activation in IECs and express copious amounts of inflammatory chemokines, but only small amounts of TNF. Although IKKβ(EE)IEC mice exhibit inflammatory cell infiltration in the lamina propria (LP) of their small intestine, they do not manifest tissue damage. Yet, upon challenge with relatively mild immune and microbial stimuli, IKKβ(EE)IEC mice succumb to destructive acute inflammation accompanied by enterocyte apoptosis, intestinal barrier disruption, and bacterial translocation. Inflammation is driven by massive TNF production, which requires additional activation of p38 and extracellular-signal–regulated kinase mitogen-activated protein kinases (MAPKs).
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Inagaki, Akiko, Takehiro Imura, Yasuhiro Nakamura, Kazuo Ohashi, and Masafumi Goto. "The Liver Surface Is an Attractive Transplant Site for Pancreatic Islet Transplantation." Journal of Clinical Medicine 10, no. 4 (February 12, 2021): 724. http://dx.doi.org/10.3390/jcm10040724.

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In the current clinical islet transplantation, intraportal transplantation is regarded as the gold-standard procedure. However, in this procedure, 50 to 70% of the transplanted islets are immediately damaged due to a strong innate immune response based on islet–blood contact. We investigated the transplant efficiency of a novel method of liver surface transplantation using a syngeneic keratinocyte sheet to avoid islet–blood contact. To examine the influence of the keratinocyte sheet, substantial amounts of syngeneic islets (8 IEQs/g) were transplanted on the liver surface of diabetic rats, while marginal amounts of islets (4 IEQs/g) were transplanted via intraportal transplantation to compare the transplant efficiency. Blood glucose, intraperitoneal glucose tolerance, immunohistochemistry, and in vivo imaging findings of the cell sheet were evaluated. The study showed that islet transplantation to the liver surface immediately followed by a syngeneic keratinocyte sheet covering was effective for curing diabetic rats, while no rats were cured in the group without the cell sheet. Notably, islet grafts transplanted via this approach appeared to penetrate into the liver parenchyma. However, the transplant efficiency did not reach that of intraportal transplantation. Further refinements of this approach by introducing mesothelial or fibroblast cell sheets in combination with a preferable scaffold for islet grafts may help to improve the transplant efficiency.
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Wen, Tsung-Han, Kuo-Wang Tsai, Yan-Jun Wu, Min-Tser Liao, Kuo-Cheng Lu, and Wan-Chung Hu. "The Framework for Human Host Immune Responses to Four Types of Parasitic Infections and Relevant Key JAK/STAT Signaling." International Journal of Molecular Sciences 22, no. 24 (December 10, 2021): 13310. http://dx.doi.org/10.3390/ijms222413310.

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The human host immune responses to parasitic infections are complex. They can be categorized into four immunological pathways mounted against four types of parasitic infections. For intracellular protozoa, the eradicable host immunological pathway is TH1 immunity involving macrophages (M1), interferon gamma (IFNγ) CD4 T cells, innate lymphoid cells 1 (NKp44+ ILC1), CD8 T cells (Effector-Memory4, EM4), invariant natural killer T cells 1 (iNKT1) cells, and immunoglobulin G3 (IgG3) B cells. For intracellular protozoa, the tolerable host immunological pathway is TH1-like immunity involving macrophages (M2), interferon gamma (IFNγ)/TGFβ CD4 T cells, innate lymphoid cells 1 (NKp44- ILC1), CD8 T cells (EM3), invariant natural killer T 1 (iNKT1) cells, and immunoglobulin A1 (IgA1) B cells. For free-living extracellular protozoa, the eradicable host immunological pathway is TH22 immunity involving neutrophils (N1), interleukin-22 CD4 T cells, innate lymphoid cells 3 (NCR+ ILC3), iNKT17 cells, and IgG2 B cells. For free-living extracellular protozoa, the tolerable host immunological pathway is TH17 immunity involving neutrophils (N2), interleukin-17 CD4 T cells, innate lymphoid cells 3 (NCR- ILC3), iNKT17 cells, and IgA2 B cells. For endoparasites (helminths), the eradicable host immunological pathway is TH2a immunity with inflammatory eosinophils (iEOS), interleukin-5/interleukin-4 CD4 T cells, interleukin-25 induced inflammatory innate lymphoid cells 2 (iILC2), tryptase-positive mast cells (MCt), iNKT2 cells, and IgG4 B cells. For ectoparasites (parasitic insects and arachnids), the eradicable host immunological pathway is TH2b immunity with inflammatory basophils, chymase- and tryptase-positive mast cells (MCct), interleukin-3/interleukin-4 CD4 T cells, interleukin-33 induced nature innate lymphoid cells 2 (nILC2), iNKT2 cells, and immunoglobulin E (IgE) B cells. The tolerable host immunity against ectoparasites and endoparasites is TH9 immunity with regulatory eosinophils, regulatory basophils, interleukin-9 mast cells (MMC9), thymic stromal lymphopoietin induced innate lymphoid cells 2, interleukin-9 CD4 T cells, iNKT2 cells, and IgA2 B cells. In addition, specific transcription factors important for specific immune responses were listed. This JAK/STAT signaling is key to controlling or inducing different immunological pathways. In sum, Tfh is related to STAT5β, and BCL6 expression. Treg is related to STAT5α, STAT5β, and FOXP3. TH1 immunity is related to STAT1α, STAT4, and T-bet. TH2a immunity is related to STAT6, STAT1α, GATA1, and GATA3. TH2b immunity is related to STAT6, STAT3, GATA2, and GATA3. TH22 immunity is associated with both STAT3α and AHR. THαβ immunity is related to STAT1α, STAT1β, STAT2, STAT3β, and ISGF. TH1-like immunity is related to STAT1α, STAT4, STAT5α, and STAT5β. TH9 immunity is related to STAT6, STAT5α, STAT5β, and PU.1. TH17 immunity is related to STAT3α, STAT5α, STAT5β, and RORG. TH3 immunity is related to STAT1α, STAT1β, STAT2, STAT3β, STAT5α, STAT5β, and ISGF. This categorization provides a complete framework of immunological pathways against four types of parasitic infections. This framework as well as relevant JAK/STAT signaling can provide useful knowledge to control allergic hypersensitivities and parasitic infections via development of vaccines or drugs in the near future.
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Maldonado Galdeano, Carolina, Silvia Inés Cazorla, José María Lemme Dumit, Eva Vélez, and Gabriela Perdigón. "Beneficial Effects of Probiotic Consumption on the Immune System." Annals of Nutrition and Metabolism 74, no. 2 (2019): 115–24. http://dx.doi.org/10.1159/000496426.

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Background: The gastrointestinal tract is one of the most microbiologically active ecosystems that plays a crucial role in the working of the mucosal immune system (MIS). In this ecosystem, the consumed probiotics stimulate the immune system and induce a network of signals mediated by the whole bacteria or their cell wall structure. This review is aimed at describing the immunological mechanisms of probiotics and their beneficial effects on the host. Summary: Once administered, oral probiotic bacteria interact with the intestinal epithelial cells (IECs) or immune cells associated with the lamina propria, through Toll-like receptors, and induce the production of different cytokines or chemokines. Macrophage chemoattractant protein 1, produced by the IECs, sends signals to other immune cells leading to the activation of the MIS, characterized by an increase in immunoglobulin A+ cells of the intestine, bronchus and mammary glands, and the activation of T cells. Specifically, probiotics activate regulatory T cells that release IL-10. Interestingly, probiotics reinforce the intestinal barrier by an increase of the mucins, the tight junction proteins and the Goblet and Paneth cells. Another proposed mechanism of probiotics is the modulation of intestinal microbiota by maintaining the balance and suppressing the growth of potential pathogenic bacteria in the gut. Furthermore, it has been demonstrated that long-term probiotics consumption does not affect the intestinal homeostasis. The viability of probiotics is crucial in the interaction with IECs and macrophages favoring, mainly, the innate immune response. Macrophages and Dendritic cells (DCs) play an important role in this immune response without inducing an inflammatory pattern, just a slight increase in the cellularity of the lamina propria. Besides, as part of the machinery that probiotics activate to protect against different pathogens, an increase in the microbicidal activity of peritoneal and spleen macrophages has been reported. In malnutrition models, such as undernourishment and obesity, probiotic was able to increase the intestinal and systemic immune response. Furthermore, probiotics contribute to recover the histology of both the intestine and the thymus damaged in these conditions. Probiotic bacteria are emerging as a safe and natural strategy for allergy prevention and treatment. Different mechanisms such as the generation of cytokines from activated pro-T-helper type 1, which favor the production of IgG instead of IgE, have been proposed. Key Messages: Probiotic bacteria, their cell walls or probiotic fermented milk have significant effects on the functionality of the mucosal and systemic immune systems through the activation of multiple immune mechanisms.
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Crowley, S. M., J. M. Allaire, X. Han, F. A. Graef, M. Stahl, L. Knodler, and B. Vallance. "A46 THE INFLAMMATORY CASPASES COORDINATE MUCOSAL RESTRICTION OF SALMONELLA THROUGH THE EPITHELIAL-INTRINSIC INFLAMMASOME AND IL-22 DRIVEN MUCIN SECRETION." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (February 2020): 54–55. http://dx.doi.org/10.1093/jcag/gwz047.045.

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Abstract Background Intestinal epithelial cells (IECs) are located at the interface between the gut lumen and the underlying mucosal defense system. Here, they play a central role in the coordination of intestinal homeostasis, tempering pro-inflammatory responses but remaining rapidly responsive to noxious stimuli such as enteric pathogens. One early response mechanism by which IECs engage in immune defense is through the activation of the inflammasome which mobilizes the inflammatory caspases; caspase-1 and -11. Aims Here, we investigated the role of the inflammasome in overall mucosal defense against the enteric pathogen Salmonella enterica serovar Typhimurium. Methods Streptomycin-pretreated C57BL/6 (wildtype), Casp1/11 deficient (−/−), Casp1−/− and Casp11−/− mice were orally infected with Salmonella and burdens determined in intestinal tissues at 18h post infection (p.i.). Results Increased pathogen loads were observed for all caspase-deficient mice compared to wildtype, which correlated with increased IEC intracellular Salmonella burdens. Interestingly, despite increased bacterial loads, pathology scores for all inflammatory caspase mice were decreased, especially with regard to ‘IEC damage’ and ‘goblet cell loss’. To determine if the increased burdens were due to the loss of IEC-intrinsic inflammasomes, enteroid monolayers were derived and infected with Salmonella. This revealed significantly increased intracellular burdens in caspase-deficient monolayers as compared to wildtype, in concert with a marked decrease in IEC shedding and cell death. Peak inflammatory caspase activity was displayed in shedding wildtype IECs, suggesting the IEC-intrinsic inflammasome restricts Salmonella infection through infected IEC expulsion. The role of inflammasome signaling in acute mucosal defense was also examined. Wildtype tissue demonstrated a dramatic increase in mucus thickness (as evaluated by Muc2 immunostaining) and antimicrobial Reg3γ and β lectin transcript levels compared to caspase-deficient mice. Mucin release and Reg3 induction has been previously linked to IL-22, therefore we measured IL-22 expression and observed increased secretion in infected wildtype mice compared to Casp1/11−/−. This correlated with increased cecal infiltration of IL-22 producing ILC3 and NK T-cells. When infected mice were treated with IL-22 neutralizing antibody, this increased Salmonella burdens and decreased infection-induced mucus secretion, while no differences were observed in Casp1/11−/− treated with neutralizing antibody or isotype control. Conclusions Therefore the intestinal epithelium utilizes inflammasome signaling to coordinate multiple layers of innate defense at the gut mucosal surface to ultimately restrict enteric pathogen infections and their systemic spread. Funding Agencies CCC, CIHR, NRCUBC
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Weiss, Jerrold P. "Endotoxin and beyond: basic and clinical concepts in innate immunity – a resumé of the 8th Conference of the IES." Journal of Endotoxin Research 11, no. 1 (February 1, 2005): 3–4. http://dx.doi.org/10.1179/096805105x35152.

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Weiss, Jerrold P. "Endotoxin and beyond: basic and clinical concepts in innate immunity — a resumé of the 8th Conference of the IES." Journal of Endotoxin Research 11, no. 1 (February 2005): 3–4. http://dx.doi.org/10.1177/09680519050110010301.

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Liu, M., D. Andreev, K. Kachler, J. Koelle, S. Rauber, A. Ramming, S. Finotto, G. Schett, and A. Bozec. "OP0132 ALLERGIC ASTHMA INDUCES THE ACCUMULATION OF SYNOVIAL RESIDENT EOSINOPHILS, TRIGGERING THE RESOLUTION OF INFLAMMATORY ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 86.3–86. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4479.

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Background:Rheumatoid arthritis (RA) is a chronic inflammatory disorder, involving synovial joints, which affects approximately 1 percent of the world population[1]. Our former work demonstrated that the Th2-eosinophil pathway is a strong anti-inflammatory mediator of inflammatory arthritis[2]. Allergic asthma is an inflammatory disease of the airway, triggered by type 2 immune response. Hitherto, clinical observations on the impact of asthma on RA showed controversial results. Herein, we investigated the action of allergic asthma on inflammatory arthritis.Objectives:We aimed to delineate the molecular and cellular responses induced by allergic asthma on inflammatory arthritis, particularly depicting the role of eosinophil subsets in arthritic synovium.Methods:Allergic asthma was induced in wild type and genetically modified mice by ovalbumin (OVA) treatment. After the initiation of allergic asthma, K/BxN serum was transferred into the asthmatic mice or control mice to trigger serum induced arthritis (SIA). Then, arthritis severity, circulating cytokines and the cytology of lung and synovium were analyzed. Eosinophil subsets were studied by flow cytometry, single cell RNA sequencing analysis, and were isolated and transferred into the synovial cavity of eosinophil deficient arthritic mice. Clinical data of patients with both RA and asthma were collected and checked for the relapse of RA after asthma treatment with anti-interleukin (IL)-5 antibody.Results:Mice induced with allergic asthma exhibited a rapid resolution of SIA. The OVA-triggered resolution disappeared in eosinophil deficient mice (ΔdblGATA), and was partially blocked by IL-5 neutralization. We could detect that IL-5 was mainly produced by type 2 innate lymphoid cell (ILC2) in the lung. Allergic asthma exclusively induced the proliferation (Ki67+) and accumulation of synovial resident eosinophils (rEos, Siglec-Fint), which switched classical macrophages into alternatively activated macrophages. Synovial induced eosinophils (iEos, Siglec-Fhigh) appeared only in the acute phase of SIA. Single cell RNA sequencing analysis showed that rEos played an anti-inflammatory role, while iEos had pro-inflammatory properties in arthritis. The roles of rEos and iEos in arthritis were confirmed by transferring rEos/iEos into the synovial cavity of arthritic mice. Patiens with both RA and asthma showed a remission relapse of RA after using humanized monoclonal IL-5 antibody for treating sever eosinophilic asthma.Conclusion:Allergic asthma induced an IL-5 mediated proliferation and accumulation of synovial rEos. The latter triggered the resolution of inflammatory arthritis. In human, eosinophils induced by asthma were essential for the sustaining of RA remission.References:[1]Myasoedova, E., et al., Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum, 2010.62(6): p. 1576-82.[2]Chen, Z., et al., Th2 and eosinophil responses suppress inflammatory arthritis. Nat Commun, 2016.7: p. 11596.Acknowledgments:Mengdan Liu and Darja Andreev contributed equally to this studyDisclosure of Interests:Mengdan Liu: None declared, Darja Andreev: None declared, Katerina Kachler: None declared, Julia Koelle: None declared, Simon Rauber: None declared, Andreas Ramming Grant/research support from: Pfizer, Novartis, Consultant of: Boehringer Ingelheim, Novartis, Gilead, Pfizer, Speakers bureau: Boehringer Ingelheim, Roche, Janssen, Susetta Finotto: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Aline Bozec: None declared
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BRAGA, Ricardo Luís Lopes, Ana Claudia Machado PEREIRA, Andréa Fonseca FERREIRA, Ana Cláudia de Paula ROSA, and Wânia Ferraz PEREIRA-MANFRO. "INTRACELLULAR PERSISTENCE OF ENTEROAGGREGATIVE ESCHERICHIA COLI INDUCES A PROINFLAMMATORY CYTOKINES SECRETION IN INTESTINAL EPITHELIAL T84 CELLS." Arquivos de Gastroenterologia 55, no. 2 (June 2018): 133–37. http://dx.doi.org/10.1590/s0004-2803.201800000-23.

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ABSTRACT BACKGROUND: The competence of enteroaggregative Escherichia coli (EAEC) to adhere to the intestinal epithelium of the host is a key role to the colonization and disease development. The virulence genes are crucial for EAEC pathogenicity during adherence, internalization and persistence in the host. The overwhelming majority of antigen encounters in a host occurs on the intestine surface, which is considered a part of innate mucosal immunity. Intestinal epithelial cells (IECs) can be activated by microorganisms and induce an immune response. OBJECTIVE: The present study investigated the interaction of invasive EAEC strains with T84 intestinal epithelial cell line in respect to bacterial invasiveness, persistence and cytokines production. METHODS: We evaluated intracellular persistence of invasive EAEC strains (H92/3, I49/3 and the prototype 042) and production of cytokines by sandwich ELISA in T84 cells upon 24 hours of infection. RESULTS: The survival rates of the prototype 042 was 0.5x103 CFU/mL while survival of I49/3 and H92/3 reached 3.2x103 CFU/mL and 1.4x103 CFU/mL, respectively. Infection with all EAEC strains tested induced significant amounts of IL-8, IL-6 and TNF-α compared to uninfected T84 cells. CONCLUSION: These data showed that infection by invasive EAEC induce a proinflammatory immune response in intestinal epithelial T84 cells.
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Ayechu-Muruzabal, Veronica, Saskia A. Overbeek, Atanaska I. Kostadinova, Bernd Stahl, Johan Garssen, Belinda van’t Land, and Linette E. M. Willemsen. "Exposure of Intestinal Epithelial Cells to 2′-Fucosyllactose and CpG Enhances Galectin Release and Instructs Dendritic Cells to Drive Th1 and Regulatory-Type Immune Development." Biomolecules 10, no. 5 (May 19, 2020): 784. http://dx.doi.org/10.3390/biom10050784.

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Intestinal epithelial cells (IEC) release immunomodulatory galectins upon exposure to CpG DNA (mimicking bacterial triggers) and short-chain galacto- and long-chain fructo-oligosaccharides (GF). This study aims to investigate the immunomodulatory properties of 2′-fucosyllactose (2′-FL), a non-digestible oligosaccharide (NDO) abundantly present in human milk, using a co-culture model developed to study the crosstalk between IEC and innate and adaptive immune cells. IECs, co-cultured with αCD3/CD28-activated peripheral blood mononuclear cells (PBMC), were apically exposed to NDOs and CpG, washed and co-cultured with immature monocyte-derived dendritic cells (moDC). Subsequently, moDC were co-cultured with naïve CD4+ T-cells. In the presence of CpG, both 2′-FL or GF-exposed IEC enhanced Th1-type IFNγ and regulatory IL-10 secretion of PBMCs, compared to CpG alone, while Th2-type IL-13 was reduced. Both NDOs increased IEC-derived galectin-3, -4, -9 and TGF-β1 of CpG-exposed IEC. Only galectin-9 correlated with all modified immune parameters and TGF-β1 secretion. MoDCs exposed to 2′-FL and CpG-conditioned IEC instructed IFNγ and IL-10 secretion by CD4+ T-cells, suggesting the development of a regulatory Th1 response. These results reveal that 2′-FL and GF could contribute to the mucosal immune development by supporting the effect of microbial CpG DNA associated with the modulation of epithelial galectin and TGF-β1 secretion.
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Binienda, Agata, Sylwia Ziolkowska, Ingvild H. Hauge, and Maciej Salaga. "The Role of Immune and Epithelial Stem Cells in Inflammatory Bowel Disease Therapy." Current Drug Targets 21, no. 14 (October 21, 2020): 1405–16. http://dx.doi.org/10.2174/1389450121666200504074922.

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Background: Inflammatory Bowel Disease (IBD) is categorized as Crohn’s disease (CD) and Ulcerative colitis (UC) and is characterized by chronic inflammation in the gastrointestinal (GI) tract. Relapsing symptoms, including abdominal pain, increased stool frequency, loss of appetite as well as anemia contribute to significant deterioration of quality of life. IBD treatment encompasses chemotherapy (e.g. corticosteroids, thiopurines) and biological agents (e.g. antibodies targeting tumour necrosis factor α, interleukin 12/23) and surgery. However, efficacy of these therapies is not satisfactory. Thus, scientists are looking for new options in IBD treatment that could induce and maintain remission. Objective: To summarize previous knowledge about role of different intestinal cells in IBD pathophysiology and application of stem cells in the IBD treatment. Results: Recent studies have emphasized an important role of innate lymphoid cells (ILCs) as well as intestinal epithelial cells (IECs) in the IBD pathophysiology suggesting that these types of cells can be new targets for IBD treatment. Moreover, last studies show that stem cells transplantation reduces inflammation in patients suffering from IBD, which are resistant to conventional therapies. Conclusion: Both hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are able to restore damaged tissue and regulate the immune system. Autologous HSCs transplantation eliminates autoreactive cells and replace them with new T-cells resulting a long-time remission. Whereas MSCs transplantation is effective therapy in one of the major complications of IBD, perianal fistulas.
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Rees, W. D., M. Stahl, K. Jacobson, B. Bressler, L. M. Sly, B. Vallance, and T. Steiner. "A202 DYSREGULATED ENDOPLASMIC RETICULUM STRESS PATHWAYS IN COLON-DERIVED ENTEROIDS FROM INFLAMMATORY BOWEL DISEASE PATIENTS DRIVE DC MATURATION LEADING TO A PRO-INFLAMMATORY PHENOTYPE." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (February 2020): 75–76. http://dx.doi.org/10.1093/jcag/gwz047.201.

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Abstract Background Intestinal epithelial cells (IECs) rely on danger signals such as adenosine triphosphate (ATP) and endoplasmic reticulum (ER) stress to form an appropriate, coordinated immune response. Moreover, ER stress in IECs contributes to the pathogenesis of inflammatory bowel disease (IBD), and an increase in extracellular ATP concentrations is a risk factor for Crohn’s disease (CD). Aims We hypothesized that cells exposed to ER stress or ATP modulate innate immune responses, creating a pro-inflammatory environment that drives dendritic cell (DC) maturation. Methods Caco-2 cells and human colon-derived enteroid monolayers were exposed to ATP or the ER stress inducer thapsigargin, stimulated with E. coli FliC flagellin, and ER stress markers CHOP, GRP78, and XBP1 s/u were measured via qPCR and western blot, and cytokine release was measured by ELISA. Next, monocyte-derived dendritic cells (moDCs) were cultured in Caco-2 or enteroid conditioned supernatants and their activation status measured via flow cytometry, and cytokine analysis was performed using Luminex platform. We also assessed ER stress markers, TLR5 expression, and cytokine expression differences between IBD and healthy controls (HC). Results We found that ER stress amplified FliC-induced IL-8 and decreased CCL20 in Caco-2 cells. Moreover, in IBD subjects, we found an increase FliC-induced IL-8 response, and decreased TNFa and CCL20. moDCs cultured with conditioned media from Caco-2 or enteroid monolayers showed a proinflammatroy phenotype, with an increase in CD80, CD86, MHCII, and a decrease in CD103. Moreover, moDCs cultured in stressed Caco-2 supernatants increased release of IL-6, TNFa, and IL-12p70, and decreased IL-10, suggesting potential to induce inflammatory Th1 and/or Th17 cells.. DC activation correlated with the amount of FliC-induced IL-8. Interestingly, there were distinct differences in cytokine expression and basal ER stress between IBD and HC enteroid monolayers, suggesting a dysregulated ER stress pathway in IBD-derived enteroids. Conclusions ER stress in Caco-2 cells and colon-derived enteroid monolayers enhances FliC-induced TLR5 responses, leading to a pro-inflammatory environment that drives DC maturation, which may link epithelial ER stress and immune cell activation in IBD. Furthermore, the cytokine and ER stress pathway differences between IBD and HC-derived enteroids suggests that prolonged periods of stress in IBD patients may rewire the IEC stem cell compartment, further perpetuating inflammation and disease. Funding Agencies CCC, CIHR
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Birkenheuer, Claire H., Connie D. Brewster, Sandra L. Quackenbush, and Joel Rovnak. "Retroviral Cyclin Controls Cyclin-Dependent Kinase 8-Mediated Transcription Elongation and Reinitiation." Journal of Virology 89, no. 10 (March 4, 2015): 5450–61. http://dx.doi.org/10.1128/jvi.00464-15.

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ABSTRACTWalleye dermal sarcoma virus (WDSV) infection is associated with the seasonal development and regression of walleye dermal sarcoma. Previous work showed that the retroviral cyclin (RV-cyclin), encoded by WDSV, has separable cyclin box and transcription activation domains. It binds to cyclin-dependent kinase 8 (CDK8) and enhances its kinase activity. CDK8 is evolutionarily conserved and is frequently overexpressed in human cancers. It is normally activated by cyclin C and is required for transcription elongation of the serum response genes (immediate early genes [IEGs])FOS,EGR1, andcJUN. The IEGs drive cell proliferation, and their expression is brief and highly regulated. Here we show that constitutive expression of RV-cyclin in the HCT116 colon cancer cell line significantly increases the level of IEG expression in response to serum stimulation. Quantitative reverse transcription-PCR (RT-PCR) and nuclear run-on assays provide evidence that RV-cyclin does not alter the initiation of IEG transcription but does enhance the overall rate of transcription elongation and maintains transcription reinitiation. RV-cyclin does not increase activating phosphorylation events in the mitogen-activated protein kinase pathway and does not inhibit decay of IEG mRNAs. At theEGR1gene locus, RV-cyclin increases and maintains RNA polymerase II (Pol II) occupancy after serum stimulation, in conjunction with increased and extendedEGR1gene expression. The RV-cyclin increases CDK8 occupancy at theEGR1gene locus before and after serum stimulation. Both of RV-cyclin's functional domains, i.e., the cyclin box and the activation domain, are necessary for the overall enhancement of IEG expression. RV-cyclin presents a novel and ancient mechanism of retrovirus-induced oncogenesis.IMPORTANCEThe data reported here are important to both virology and cancer biology. The novel mechanism pinpoints CDK8 in the development of walleye dermal sarcoma and sheds light on CDK8's role in many human cancers. CDK8 controls expression from highly regulated genes, including the interferon-stimulated genes. Its function is likely the target of many viral interferon-resistance mechanisms. CDK8 also controls cellular responses to metabolic stimuli, stress, and hypoxia, in addition to the serum response. The retroviral cyclin (RV-cyclin) represents a highly selected probe of CDK8 function. RV-cyclin does not control CDK8 specificity but instead enhances CDK8's effects on regulated genes, an important distinction for its use to delineate natural CDK8 targets. The outcomes of this research are applicable to investigations of normal and abnormal CDK8 functions. The mechanisms defined here will contribute directly to the dermal sarcoma model in fish and clarify an important path for oncogenesis and innate resistance to viruses.
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Chen, Y., J. M. Allaire, X. Han, H. Yang, S. M. Crowley, and B. Vallance. "A40 IDENTIFYING NOVEL ROLES FOR TLR2 SIGNALING IN THE INTESTINAL EPITHELIUM USING ORGANOIDS." Journal of the Canadian Association of Gastroenterology 5, Supplement_1 (February 21, 2022): 47–48. http://dx.doi.org/10.1093/jcag/gwab049.039.

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Abstract Background Inflammatory bowel disease (IBD) is thought to result from an imbalance between protective and damaging immune responses to the resident microbiota and other luminal antigens. Increasing evidence suggests that toll-like-receptor (TLR)-mediated innate immune dysfunction contributes to the pathogenesis of IBD. Among the receptors in the TLR family, TLR2 and its signalling pathway appears to play an important protective role in the gastrointestinal (GI) tract. Notably, our group previously discovered that Tlr2 expression by nonhematopoietic cells played an important protective role in the Citrobacter rodentium model of infectious colitis. Aims To determine if intestinal epithelial cells (IECs) control Tlr2 dependent tissue protective responses, we sought to characterize the role of Tlr2 signalling in intestinal organoids. In addition, to better define the role of Tlr2 during C. rodentium infection, we developed a novel in vitro model of C. rodentium infection using organoid-derived monolayers. Methods Organoids were derived from the colonic tissue of wild type (C57BL/6J) and Tlr2 deficient (-/-) mice and then stimulated with Tlr2 agonists, and their responses were evaluated by qPCR, ELISA, Western blot and immunostaining. In addition, 2D monolayers were grown from organoids, and infected with C. rodentium to explore whether Tlr2 signaling regulates other protective IEC functions such as barrier proteins and cell death in response to noxious stimuli. Results Stimulation of WT, but not Tlr2-/- mouse orgnaoids led to increased transcription of chemokine and cytokine genes Ccl20, Mcp-1, Cxcl1 and Tnf-α. This was accompanied by increased protein secretion through a NF-κB and p38 MAP kinase dependent mechanism. Interestingly, organoids derived from the distal colon displayed stronger Tlr2 responses than organoids from the proximal colon. During C. rodentium infection of monolayers, Tlr2 signaling had no effect on the distribution of tight junction proteins such as ZO-1 or Claudin3, however, Tlr2 did regulate levels of IEC apoptosis upon C. rodentium infection. Conclusions Our study demonstrates that colonic organoids express functional Tlr2, which upon stimulation, leads to pro-inflammatory responses as well as control over cell death. Our novel C. rodentium infection model enables us to further study the role of IEC in promoting host defense during bacterial infection. Futher work will examine how interactions with Tlr2 dependent cytokines (ie. IL-6, IL-22) impact IEC responses to C. rodentium. Funding Agencies CCC, CIHRCH.I.L.D
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Wottawa, F., B. Becker, M. Bakr, J. Kugler, L. Mayr, S. Paludan, R. Blumberg, et al. "DOP46 Metabolic adaptation to ER stress licences STING signalling in intestinal epithelial cells." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i095—i096. http://dx.doi.org/10.1093/ecco-jcc/jjab232.085.

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Abstract Background Chronic endoplasmic reticulum stress (ER) in the intestinal epithelium is a pathophysiological hallmark of IBD. cGAS/STING is an innate immune pathway involved in the detection of double stranded DNA fragments leading to the subsequent induction of type I IFN responses. We here tested the hypothesis that chronic ER stress impairs cGAS/STING signalling in the intestinal epithelium. Methods Mice with a conditional intestinal epithelial deletion of Xbp1 (Xbp1 ΔIEC, Xbp1fl/fl) were used to assess intestinal epithelial STING expression in-vivo. Small intestinal organoids (Xbp1ΔIEC, Xbp1fl/fl) and cell lines (Mode K, iCtrl and iXbp1) were used to assess cGAS/STING signalling in-vitro using STING agonist (dsDNA, DMXAA). Murine cytomegalovirus (mCMV) infection assays were performed in iCtrl and iXbp1cells and Xbp1ΔIEC, Xbp1fl/fl mice to functionally link impaired cGAS/STING to pathogen response. LC-MS profiling was performed in iCtrl and iXbp1cells to identify underlying metabolic programs affecting cGAS/STING responses in ER-stressed cells. IBD biopsy samples (cross-sectional, longitudinal therapy response cohort) were used to validate key molecular phenotypes in human IBD. Results Compared to Xbp1 fl/fl mice, Xbp1ΔIEC show completely abrogated STING expression in the basal crypt compartment of the small intestinal epithelium. In line with that iXbp1 ModeK cells displayed impaired pathway activation (TBK1) and interferon inducible gene expression (Cxcl10) in response to cGAS/STING stimulation and towards mCMV infection, leading to increased viral replication compared to iCtrl cells. In-vivo mCMV infection led to augmented small intestinal histopathological disease activity in Xbp1ΔIEC, but not Xbp1fl/fl mice. Using LC-MS, we show that ER-stress induces a metabolic adaptation towards increased serin/glycin metabolism, which is used to counterbalance reactive oxygen species (ROS) via glutathione (GSH) synthesis. Pharmacological interception of key pathways of GSH synthesis of deprivation of serin/glycin phenocopies ER-stress in abrogating STING signalling in IECs. Lastly, we show that key aspects of metabolic adaptation to ER-stress are present in intestinal biopsies of IBD patients. Conclusion Our data describe a novel mechanism of metabolic adaptation to compensate ER-stress and maintain intestinal epithelial cGAS/STING signalling. We therefore put forward a model of ER-stress driven immunodeficiency via cGAS/STING signalling which renders the intestinal mucosa susceptible towards CMV infection in the context of IBD.
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Cannon, Abigail, Esther Shim, Paulius Kuprys та Mashkoor Choudhry. "P160 γδ T CELLS, IL-22, THE PROBIOTIC, LACTOBACILLUS DELBRUECKII, AND THE ROLE THEY PLAY IN ATTENUATION OF ALCOHOL INDUCED EXACERBATION OF DSS-COLITIS". Inflammatory Bowel Diseases 26, Supplement_1 (січень 2020): S34. http://dx.doi.org/10.1093/ibd/zaa010.086.

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Abstract Ulcerative colitis is characterized by cycles of active disease flare and inactive disease remission. During UC remission, IL-22 expression can be upregulated, acting as a hallmark of entrance into a UC remission period. Recently, we found that in our mouse model of binge alcohol consumption after DSS-induced colitis, alcohol increases severity of UC flare symptoms. In this study, we assessed whether alcohol influenced IL-22 expression and thereby perpetuates UC flare. Male C57BL/6 mice received 2% DSS or water ad libitum for 5 days. On day 5, DSS was removed to mimic entrance into remission. Additionally on day 5, DSS and Sham mice were subdivided into mice gavaged with ethanol (∼3g/kg) or with water on days 5, 6, and 7. Three hours after the last gavage on day 7, mice were humanely euthanized. Large intestine lamina propria (LP) cells were isolated. The percentage of total IL-22+ LP cells was significantly decreased (p&lt;0.05) in DSS Ethanol compared to DSS Vehicle. No differences in IL-22+ T cells, Innate Lymphoid Cells Type 3, or neutrophils were observed. Examination of I γδ T cells revealed DSS Vehicle treated mice had a significantly increased percentage of IL-22+ γδ T cells, while DSS Ethanol treated mice were unable to mount this response. Therefore, we hypothesized that by re-establishing IL-22, through either rIL-22 or a probiotic, we could alleviate the alcohol-induced exacerbation of UC. Firstly, rIL-22 administration substantially restored weight loss of DSS Ethanol treated mice back to that of DSS Vehicle (∼12.5% back to ∼6% on day 7). Increased colonic shortening (p&lt;0.001) and increased Enterobacteriaceae copy number were also attenuated following binge alcohol and colitis with IL-22 treatment. Knockout of STAT3 in IECs resulted in loss of IL-22 protection, demonstrating STAT3 is required for protection. Secondly, we utilized Lactobacillus delbrueckii, a common probiotic known to play a role in IL-22 release. Treatment with Lacto attenuated both weight loss and colon length in DSS Ethanol mice back to levels of DSS alone (p&lt;0.01 and p&lt;0.001, respectively). Additionally, Lacto treatment mitigated increases in Enterobacteriaceae copy number seen in DSS Ethanol mice and trended towards an increase in IL-22 in DSS Ethanol + Lacto mice. Levels of pSTAT3 were decreased in DSS Ethanol treated mice compared to DSS Vehicle, but administration of Lacto in DSS Ethanol mice increased levels of pSTAT3 back to that of the DSS Vehicle group. Treatment with Lacto supernatant alone was not sufficient to mitigate the exacerbation of UC following ethanol. Our findings suggest that both rIL-22 and Lactobacillus delbrueckii utilize the IL-22/pSTAT3 signaling pathway to attenuate alcohol-induced increases in ulcerative colitis symptoms. (R21AA022324, R21AA025806, T32AA013527, F30AA027442, F31AA025536)
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Vanlandschoot, Romain. "Verdraagzaamheid en pragmatische samenwerking in de Vlaamse beweging. Hugo Verriest en August Vermeylen 1895-1914. Deel 3." WT. Tijdschrift over de geschiedenis van de Vlaamse beweging 72, no. 3 (September 10, 2013): 207–41. http://dx.doi.org/10.21825/wt.v72i3.12194.

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Deel 3: Hoogtepunt 1910-1914De samenwerking tussen August Vermeylen en Hugo Verriest kende in de laatste jaren voor de Eerste Wereldoorlog een waar hoogtepunt. De toespraak van Verriest op de Brusselse wereldtentoonstelling, 5 juli 1910, in aanwezigheid van koning Albert I, maakte veel ophef, maar stootte ook de liberale opinie voor het hoofd door zijn eenzijdige kijk op de West-Vlaamse literatuur. In 1912 stelde Vermeylen zijn bekende leuze uit 1900 bij: “om iets te zijn moeten we Vlaming zijn. Wij willen Vlaming zijn om Europeeër te worden”. Hij positioneerde de Vlaamse beweging in het groeiende spanningsveld tussen Frankrijk en Duitsland.Het jaar daarop zette Vermeylen zich in, als voorzitter van de Vereniging van Vlaamse Letterkundigen, om op 17 augustus 1913 een grootse hulde te brengen aan de pastoor van Ingooigem, in aanwezigheid van duizenden Vlamingen en Nederlanders. Hij prees hierbij de verdraagzaamheid die Verriest opbracht voor andersdenkenden. Hij waardeerde in hem de “innige samenhang van kunst en leven, die letterkundigen en strijders voor hogere cultuur in Vlaanderen verenigt”. Op de feestelijkheid waren alle generaties sedert het overlijden van Albrecht Rodenbach (1880) aanwezig, “van overal waar Nederlandse taal klinkt”.De laatste vooroorlogse samenwerking betrof de agitatie rond het wetsontwerp van minister Prosper Poullet op het lager onderwijs en de desbetreffende taalregeling voor de Vlaamse kinderen, inzonderheid te Brussel. Op de meeting van 10 februari 1914 voerden de socialistische voorman Alberic Deswarte, de katholieke priester Hugo Verriest en August Vermeylen het woord. Verriest had het over het bevrijdende ‘nadere springtij’ in Vlaanderen. Met zijn allen ijverden zij voor de fundamentele rechten van alle volkskinderen op onderwijs in de moedertaal, vorming en behoorlijke beroepsopleiding. Vermeylen waarschuwde scherp voor het verlies van Brussel door de sterke verfransingsdruk.Als algemeen besluit mag gelden dat de samenwerking van Vermeylen en Verriest in de jaren 1895-1914 een belangrijke bijdrage betekende in de vooruitgang van de Vlaamse beweging.________Tolerance and pragmatic cooperation in the Flemish Movement. Hugo Verriest and August Vermeylen 1895-1914. Part 3: High point 1910-1914During the last years before the First World War the cooperation between August Vermeylen and Hugo Verriest culminated in a true high point. Much was made of Verriest’s address at the Brussels’ world exhibition on 5 July 1910 in the presence of King Albert I, but the speech also offended the liberals because of its one-sided view of West Flemish literature. In 1912 Vermeylen adjusted his well-known slogan from 1900: “in order to be anything, we need to be Flemish. We wish to be Flemish in order to become Europeans”. He positioned the Flemish movement in the growing area of tension between France and Germany.On 17 August of the following year, Vermeylen as chairman of the Association of Flemish Authors dedicated his efforts to pay an elaborate tribute to the parish priest of Ingooigem in the presence of thousands of Flemish and Dutch people. In doing so, he praised the tolerance with which Verriest treated dissidents. He appreciated that Verriest manifested “the close cohesion of art and life, which unites authors and fighters for higher culture in Flanders”. At this festive occasion all generations since the death of Albrecht Rodenbach (1880) were present, “from everywhere where the Dutch language is spoken”.The last time they cooperated before the war related to the turmoil about Minister Proper Poullets’ draft law on elementary education and the relevant language regime for Flemish school children, in particular in Brussels. At the meeting on 10 February 1914, the socialist leader Alberic Deswarte, the Catholic priest Hugo Verriest and August Vermeylen took the floor. Verriest spoke about the liberating ‘approaching spring tide’ in Flanders. All together they dedicated their efforts to the fundamental rights of all working-class children to enjoy education in their native language, to formation and a decent professional training. Vermeylen warned in strong terms about the loss of Brussels because of the strong pressure towards Frenchification.We may draw the general conclusion that the cooperation between Vermeylen and Verriest during the period of 1895-1914 made a major contribution towards the progress of the Flemish movement.
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Lin, Chia-Hao, Mei-Chi Chen, Ling-Li Lin, David A. Christian, Booki Min, Christopher A. Hunter, and Li-Fan Lu. "Gut epithelial IL-27 confers intestinal immunity through the induction of intraepithelial lymphocytes." Journal of Experimental Medicine 218, no. 11 (September 23, 2021). http://dx.doi.org/10.1084/jem.20210021.

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IL-27 controls a diverse range of immune responses in many disease settings. Here, we identify intestinal epithelial cells (IECs) as one of the major IL-27 cellular sources in the gut-associated tissue. Unlike IL-27 secreted by innate immune cells, gut epithelial IL-27 is dispensable for T-bet+ regulatory T cell (T reg cell) differentiation or IL-10 induction. Rather, IEC-derived IL-27 specifically promotes a distinct CD8αα+CD4+ intraepithelial lymphocyte (IEL) population that acquires their functional differentiation at the intestinal epithelium. Loss of IL-27 in IECs leads to a selective defect in CD8αα+CD4+ IELs over time. Consequently, mice with IEC-specific IL-27 ablation exhibited elevated pathogen burden during parasitic infection, and this could be rescued by transfer of exogenous CD8αα+CD4+ IELs. Collectively, our data reveal that in addition to its known regulatory properties in preventing immune hyperactivity, gut epithelial IL-27 confers barrier immunity by inducing a specific IEL subset and further suggest that IL-27 produced by different cell types plays distinct roles in maintaining intestinal homeostasis.
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Panea, Casandra, Ruoyu Zhang, Jeffrey VanValkenburgh, Min Ni, Christina Adler, Yi Wei, Francisca Ochoa та ін. "Butyrophilin-like 2 regulates site-specific adaptations of intestinal γδ intraepithelial lymphocytes". Communications Biology 4, № 1 (26 липня 2021). http://dx.doi.org/10.1038/s42003-021-02438-x.

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AbstractTissue-resident γδ intraepithelial lymphocytes (IELs) orchestrate innate and adaptive immune responses to maintain intestinal epithelial barrier integrity. Epithelia-specific butyrophilin-like (Btnl) molecules induce perinatal development of distinct Vγ TCR+ IELs, however, the mechanisms that control γδ IEL maintenance within discrete intestinal segments are unclear. Here, we show that Btnl2 suppressed homeostatic proliferation of γδ IELs preferentially in the ileum. High throughput transcriptomic characterization of site-specific Btnl2-KO γδ IELs reveals that Btnl2 regulated the antimicrobial response module of ileal γδ IELs. Btnl2 deficiency shapes the TCR specificities and TCRγ/δ repertoire diversity of ileal γδ IELs. During DSS-induced colitis, Btnl2-KO mice exhibit increased inflammation and delayed mucosal repair in the colon. Collectively, these data suggest that Btnl2 fine-tunes γδ IEL frequencies and TCR specificities in response to site-specific homeostatic and inflammatory cues. Hence, Btnl-mediated targeting of γδ IEL development and maintenance may help dissect their immunological functions in intestinal diseases with segment-specific manifestations.
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Hosmillo, Myra, Yasmin Chaudhry, Komal Nayak, Frederic Sorgeloos, Bon-Kyoung Koo, Alessandra Merenda, Reidun Lillestol, Lydia Drumright, Matthias Zilbauer, and Ian Goodfellow. "Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses." mBio 11, no. 2 (March 17, 2020). http://dx.doi.org/10.1128/mbio.00215-20.

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ABSTRACT Human noroviruses (HuNoV) are a leading cause of viral gastroenteritis worldwide and a significant cause of morbidity and mortality in all age groups. The recent finding that HuNoV can be propagated in B cells and mucosa-derived intestinal epithelial organoids (IEOs) has transformed our ability to dissect the life cycle of noroviruses. Using transcriptome sequencing (RNA-Seq) of HuNoV-infected intestinal epithelial cells (IECs), we have found that replication of HuNoV in IECs results in interferon (IFN)-induced transcriptional responses and that HuNoV replication in IECs is sensitive to IFN. This contrasts with previous studies that suggested that the innate immune response may play no role in the restriction of HuNoV replication in immortalized cells. We demonstrated that inhibition of Janus kinase 1 (JAK1)/JAK2 enhanced HuNoV replication in IECs. Surprisingly, targeted inhibition of cellular RNA polymerase II-mediated transcription was not detrimental to HuNoV replication but instead enhanced replication to a greater degree than blocking of JAK signaling directly. Furthermore, we demonstrated for the first time that IECs generated from genetically modified intestinal organoids, engineered to be deficient in the interferon response, were more permissive to HuNoV infection. Taking the results together, our work revealed that IFN-induced transcriptional responses restrict HuNoV replication in IECs and demonstrated that inhibition of these responses mediated by modifications of the culture conditions can greatly enhance the robustness of the norovirus culture system. IMPORTANCE Noroviruses are a major cause of gastroenteritis worldwide, and yet the challenges associated with their growth in culture have greatly hampered the development of therapeutic approaches and have limited our understanding of the cellular pathways that control infection. Here, we show that human intestinal epithelial cells, which represent the first point of entry of human noroviruses into the host, limit virus replication by induction of innate responses. Furthermore, we show that modulating the ability of intestinal epithelial cells to induce transcriptional responses to HuNoV infection can significantly enhance human norovirus replication in culture. Collectively, our findings provide new insights into the biological pathways that control norovirus infection but also identify mechanisms that enhance the robustness of norovirus culture.
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Hendrix, Justin R., Anne-Marie Overstreet, Antonia Boger-May, and David Boone. "Characterizing the Extent of Cell Death in Innate Immune Mediated Colitis." Proceedings of IMPRS 1, no. 1 (December 7, 2018). http://dx.doi.org/10.18060/22703.

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Background and Hypothesis: Intestinal epithelial cell (IEC) turnover occurs every four-to-five days. In inflammatory bowel disease (IBD), IECs undergo increased cell death due to inflammation of intestinal villi and colonic crypts. This cell death leads to increased permeability of the intestinal barrier. This study examined the pathogenesis of IBD, focusing on innate immunity using mice with spontaneous innate immune colitis. The objective was to observe if there is a significant difference in expression of apoptosis in colitic mice vs. control mice. Experimental Design: Mice expressing the NF-kB inhibitor TNFAIP3 in the villi of IECs were interbred with RAG1-/- mice. TNFAIP3 x RAG1-/- (TRAG) mice developed 100% penetrant colitis by 6 weeks of age that was not observed in TNFAIP3 or RAG1-/- littermates. The presence of activated caspase-3 in distal colons was detected using immunofluorescence and quantified using ImageJ to compare differences between 4- and 8-week-old RAG vs.TRAG mice. Results: Increased numbers of caspase-3+ cells were found in TRAG mice compared to RAG mice. After treatment with antibiotics, similar levels of capase-3 were detected in both groups. Conclusion and Potential Impact: This investigation suggests that cell death in TRAG mice were increased due to deficient innate immunity in IECs. Thus, bacteria play a direct role by killing IECs or an indirect role by causing inflammation. Understanding how innate immune activation drives cell death in IECs, may lead to a better understanding of the complex regulation of IBD, and improved therapeutic agents targeting novel cell types in the remission of chronic IBD.
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Sayed, Nazish, Wing Tak Wong, and John P. Cooke. "Abstract 246: Transdifferentiation of Human Fibroblasts to Endothelial Cells: Role of Innate Immunity." Circulation Research 113, suppl_1 (August 2013). http://dx.doi.org/10.1161/res.113.suppl_1.a246.

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Cell fate is fluid, and may be altered experimentally by the forced expression of master regulators mediating cell lineage. Such nuclear reprogramming has been achieved using viral vectors encoding transcription factors. We recently discovered that the viral vectors are more than passive vehicles for transcription factors, as they participate actively in the process of nuclear reprogramming to pluripotency. Viral vectors, by activating innate immunity, cause global changes in the expression of epigenetic modifiers, favoring an open chromatin state (Cell, 151 2012). Based on the recognition that activation of innate immunity increases epigenetic plasticity, we hypothesized that small molecule activators of toll-like receptor 3 (TLR3), together with external microenvironmental cues that drive EC specification, might be sufficient to induce transdifferentiation of fibroblasts into ECs (iECs). Here we show that TLR3 agonist Poly I:C, combined with exogenous EC growth factors, transdifferentiated human fibroblasts into ECs (in the absence of viral vectors or transcription factors). These iECs were comparable to HMVEC in immunohistochemical, genetic and functional assays, including the ability to form capillary-like structures and to incorporate acetylated-LDL. Furthermore, iECs significantly improved limb perfusion and neovascularization in the murine ischemic hindlimb compared to parental fibroblasts. Finally, using genetic knockdown studies, we find that the effective transdifferentiation of human fibroblasts to endothelial cells requires innate immune activation. This study suggests that manipulation of innate immune signaling may be generally used to modify cell fate. Our observations raise the question as to whether epigenetic plasticity and cell fate fluidity generally participate in the immune defense against pathogens. Because similar signaling pathways are activated by damage associated molecular patterns, epigenetic plasticity induced by innate immunity may play a fundamental role in transdifferentiation during wound healing and regeneration. Finally, this study is a first step toward development of a small molecule strategy for therapeutic transdifferentiation in vivo.
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Deets, Katherine A., Randilea Nichols Doyle, Isabella Rauch, and Russell E. Vance. "Inflammasome activation leads to cDC1-independent cross-priming of CD8 T cells by epithelial cell-derived antigen." eLife 10 (December 23, 2021). http://dx.doi.org/10.7554/elife.72082.

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The innate immune system detects pathogens and initiates adaptive immune responses. Inflammasomes are central components of the innate immune system, but whether inflammasomes provide sufficient signals to activate adaptive immunity is unclear. In intestinal epithelial cells (IECs), inflammasomes activate a lytic form of cell death called pyroptosis, leading to epithelial cell expulsion and the release of cytokines. Here, we employed a genetic system to show that simultaneous antigen expression and inflammasome activation specifically in IECs is sufficient to activate CD8+ T cells. By genetic elimination of direct T cell priming by IECs, we found that IEC-derived antigens were cross-presented to CD8+ T cells. However, cross-presentation of IEC-derived antigen to CD8+ T cells only partially depended on IEC pyroptosis. In the absence of inflammasome activation, cross-priming of CD8+ T cells required Batf3+ dendritic cells (conventional type one dendritic cells [cDC1]), whereas cross-priming in the presence of inflammasome activation required a Zbtb46+ but Batf3-independent cDC population. These data suggest the existence of parallel inflammasome-dependent and inflammasome-independent pathways for cross-presentation of IEC-derived antigens.
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Lee, Minji, Hyun-Ja Ko, Sung-Wook Hong, Jungeun Park, Seokjin Ham, Mingyu Kim, Dong-il Kwon, et al. "Dietary antigens suppress the proliferation of type 2 innate lymphoid cells by restraining homeostatic IL-25 production." Scientific Reports 12, no. 1 (May 6, 2022). http://dx.doi.org/10.1038/s41598-022-11466-4.

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AbstractDietary antigens affect the adaptive immunity of the host by inducing regulatory T cells and IgE-producing B cells. However, their roles in innate immune compartments such as innate lymphoid cells (ILCs) and intestinal epithelial cells (IECs) are unclear. Here, using antigen-free (AF) mice, which are germ-free (GF) mice fed with amino-acid-based diet, we found dietary proteins suppress the development of GATA-3-expressing ILC2s independent of the adaptive immune cells. These cells produce more type 2 cytokines and upregulated proliferation and activation markers such as Ki-67, CD69, and CD25. With this, AF mice had increased expressions of tuft cell-specific transcripts such as Il25, Il33, Dclk1, Trpm5, and Pou2f3 in IECs. Accordingly, expanded ILC2s upregulated IL-17RB, a receptor of IL-25, and their proliferation was blocked by IL-25 neutralizing or IL-17RB blocking antibodies. These results suggest a new dialogue between dietary antigens, IECs, and ILCs in which dietary antigens suppress ILC2 activation and proliferation by restraining homeostatic IL-25 production, potentially limiting type 2 immunity by food antigens.

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