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1
Brunette, Rebecca L., Janet M. Young, Deborah G. Whitley, Igor E. Brodsky, Harmit S. Malik, and Daniel B. Stetson. "Extensive evolutionary and functional diversity among mammalian AIM2-like receptors." Journal of Experimental Medicine 209, no. 11 (October 8, 2012): 1969–83. http://dx.doi.org/10.1084/jem.20121960.
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Innate immune detection of nucleic acids is important for initiation of antiviral responses. Detection of intracellular DNA activates STING-dependent type I interferons (IFNs) and the ASC-dependent inflammasome. Certain members of the AIM2-like receptor (ALR) gene family contribute to each of these pathways, but most ALRs remain uncharacterized. Here, we identify five novel murine ALRs and perform a phylogenetic analysis of mammalian ALRs, revealing a remarkable diversification of these receptors among mammals. We characterize the expression, localization, and functions of the murine and human ALRs and identify novel activators of STING-dependent IFNs and the ASC-dependent inflammasome. These findings validate ALRs as key activators of the antiviral response and provide an evolutionary and functional framework for understanding their roles in innate immunity.
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Silva, Grace, Natália Carneiro, Dario Zamboni, and João Silva. "NLRP3 and AIM2 mediate nitric oxide production and macrophage resistance to T. cruzi infection (INM3P.442)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 57.5. http://dx.doi.org/10.4049/jimmunol.192.supp.57.5.
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Abstract The Toll-like receptors (TLRs), 2, 4 and 9 are important to immunity against Trypanosoma cruzi, etiologic agent of Chagas disease. Intracellular receptors, including NLRP3 and AIM2, associate to ASC forming a complex that active caspase-1, called inflammasome. This complex is required for cleavage of the active forms of the IL-1β and IL-18. Recently, we show that ASC inflammasome is necessary to control T. cruzi infection, however the receptors that participate in this signalizing are not complete clear. Here, we investigated the participation of NLRP3 and AIM2 in the immune response against T. cruzi. First, we found high IL-1β production and caspase-1 activation in BMMs from WT mice, but not from NLRP3-/- and AIM2-/- mice. To understand the role of the inflammasome pathway during T. cruzi infection, WT, caspase-1-/-, ASC-/-, AIM2-/- and NLRP3-/- mice were infected with Y strain of T.cruzi. Our results showed that ASC-/- and caspase-1-/- mice presented higher mortality, whereas WT, AIM3-/- and NLRP3-/- are resistant to infection, suggesting more than one NLR is necessary to confer resistance for T. cruzi infection. In addition, caspase-1-/-, ASC-/-, AIM2-/- and NLRP3 BMMs presented higher parasitism and reduced amount of Nitric oxide (NO) production. Together, these results suggest that AIM2 and NLRP3 via ASC inflammasome participate of the infection against T. cruzi. Financial Support: FAPESP
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Jiang, Hui, Patrycja Swacha, and Nelson O. Gekara. "Nuclear AIM2‐Like Receptors Drive Genotoxic Tissue Injury by Inhibiting DNA Repair." Advanced Science 8, no. 22 (October 18, 2021): 2102534. http://dx.doi.org/10.1002/advs.202102534.
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Gray, Elizabeth E., Damion Winship, Jessica M. Snyder, Stephanie J. Child, Adam P. Geballe, and Daniel B. Stetson. "The AIM2-like Receptors Are Dispensable for the Interferon Response to Intracellular DNA." Immunity 45, no. 2 (August 2016): 255–66. http://dx.doi.org/10.1016/j.immuni.2016.06.015.
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Gray, Elizabeth, and Daniel B. Stetson. "The AIM2-like receptors are dispensable for activation of the interferon stimulatory DNA (ISD) pathway." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 203.10. http://dx.doi.org/10.4049/jimmunol.196.supp.203.10.
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Abstract Detection of intracellular DNA triggers activation of the STING-dependent interferon-stimulatory DNA (ISD) pathway, which is essential for antiviral immune responses; on the other hand, inappropriate immune responses to self DNA result in autoimmunity. Multiple DNA sensors have been proposed to activate the ISD pathway, including cyclic GMP-AMP synthase (cGAS) and a family of DNA binding receptors called the AIM2-like receptors (ALRs). Analysis of cGAS-deficient mice has revealed that cGAS is a key DNA sensor that is required for activation of the ISD pathway; however, whether the ALRs contribute to this pathway remains unclear. Here, we generated mice lacking all 13 mouse ALR genes as a novel tool to explore the function of the ALRs. We show that all ALRs are dispensable for the type I interferon (IFN) response to transfected DNA ligands, DNA virus infection, and lentivirus infection. We also show that the DNA sensor cGAS, but not the ALRs, is required to drive autoimmune disease in the Trex1-deficient mouse model of Aicardi-Goutieres Syndrome. Finally, we used CRISPR to disrupt the human AIM2-like receptor IFI16 in primary human fibroblasts and show that IFI16 is dispensable for the IFN response to transfected DNA ligands as well as human cytomegalovirus (HCMV) infection. Thus, our data reveal that ALRs are dispensable for activation of the ISD pathway and demonstrate that cGAS is the primary DNA sensor that drives the IFN response to DNA.
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Jang, Ji-Hyun, Hee Woong Shin, Jung Min Lee, Hyeon-Woo Lee, Eun-Cheol Kim, and Sang Hyuk Park. "An Overview of Pathogen Recognition Receptors for Innate Immunity in Dental Pulp." Mediators of Inflammation 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/794143.
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Pathogen recognition receptors (PRRs) are a class of germ line-encoded receptors that recognize pathogen-associated molecular patterns (PAMPs). The activation of PRRs is crucial for the initiation of innate immunity, which plays a key role in first-line defense until more specific adaptive immunity is developed. PRRs differ in the signaling cascades and host responses activated by their engagement and in their tissue distribution. Currently identified PRR families are the Toll-like receptors (TLRs), the C-type lectin receptors (CLRs), the nucleotide-binding oligomerization domain-like receptors (NLRs), the retinoic acid-inducible gene-I-like receptors (RLRs), and the AIM2-like receptor (ALR). The environment of the dental pulp is substantially different from that of other tissues of the body. Dental pulp resides in a low compliance root canal system that limits the expansion of pulpal tissues during inflammatory processes. An understanding of the PRRs in dental pulp is important for immunomodulation and hence for developing therapeutic targets in the field of endodontics. Here we comprehensively review recent finding on the PRRs and the mechanisms by which innate immunity is activated. We focus on the PRRs expressed on dental pulp and periapical tissues and their role in dental pulp inflammation.
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Wang, Li-Jie, Chia-Wei Hsu, Chiu-Chin Chen, Ying Liang, Lih-Chyang Chen, David M. Ojcius, Ngan-Ming Tsang, Chuen Hsueh, Chih-Ching Wu, and Yu-Sun Chang. "Interactome-wide Analysis Identifies End-binding Protein 1 as a Crucial Component for the Speck-like Particle Formation of Activated Absence in Melanoma 2 (AIM2) Inflammasomes." Molecular & Cellular Proteomics 11, no. 11 (August 6, 2012): 1230–44. http://dx.doi.org/10.1074/mcp.m112.020594.
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Inflammasomes are cytoplasmic receptors that can recognize intracellular pathogens or danger signals and are critical for interleukin 1β production. Although several key components of inflammasome activation have been identified, there has not been a systematic analysis of the protein components found in the stimulated complex. In this study, we used the isobaric tags for relative and absolute quantification approach to systemically analyze the interactomes of the NLRP3, AIM2, and RIG-I inflammasomes in nasopharyngeal carcinoma cells treated with specific stimuli of these interactomes (H2O2, poly (dA:dT), and EBV noncoding RNA, respectively). We identified a number of proteins that appeared to be involved in the interactomes and also could be precipitated with anti-apoptosis-associated speck-like protein containing caspase activation and recruitment domain antibodies after stimulation. Among them, end binding protein 1 was an interacting component in all three interactomes. Silencing of end binding protein 1 expression by small interfering RNA inhibited the activation of the three inflammasomes, as indicated by reduced levels of interleukin 1β secretion. We confirmed that end binding protein 1 directly interacted with AIM2 and ASC in vitro and in vivo. Most importantly, fluorescence confocal microscopy showed that end binding protein 1 was required for formation of the speck-like particles that represent activation of the AIM2 inflammasome. In nasopharyngeal carcinoma tissues, immunohistochemical staining showed that end binding protein 1 expression was elevated and significantly correlated with AIM2 and ASC expression in nasopharyngeal carcinoma tumor cells. In sum, we profiled the interactome components of three inflammasomes and show for the first time that end binding protein 1 is crucial for the speck-like particle formation that represents activated inflammasomes.
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Lu, Jianlin, Jessica M. Gullett, and Thirumala-Devi Kanneganti. "Filoviruses: Innate Immunity, Inflammatory Cell Death, and Cytokines." Pathogens 11, no. 12 (November 23, 2022): 1400. http://dx.doi.org/10.3390/pathogens11121400.
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Filoviruses are a group of single-stranded negative sense RNA viruses. The most well-known filoviruses that affect humans are ebolaviruses and marburgviruses. During infection, they can cause life-threatening symptoms such as inflammation, tissue damage, and hemorrhagic fever, with case fatality rates as high as 90%. The innate immune system is the first line of defense against pathogenic insults such as filoviruses. Pattern recognition receptors (PRRs), including toll-like receptors, retinoic acid-inducible gene-I-like receptors, C-type lectin receptors, AIM2-like receptors, and NOD-like receptors, detect pathogens and activate downstream signaling to induce the production of proinflammatory cytokines and interferons, alert the surrounding cells to the threat, and clear infected and damaged cells through innate immune cell death. However, filoviruses can modulate the host inflammatory response and innate immune cell death, causing an aberrant immune reaction. Here, we discuss how the innate immune system senses invading filoviruses and how these deadly pathogens interfere with the immune response. Furthermore, we highlight the experimental difficulties of studying filoviruses as well as the current state of filovirus-targeting therapeutics.
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Latz, Eicke. "New Insights into the Biology of Toll-Like Receptors and Inflammasomes." Blood 114, no. 22 (November 20, 2009): SCI—23—SCI—23. http://dx.doi.org/10.1182/blood.v114.22.sci-23.sci-23.
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Abstract Abstract SCI-23 Innate immunity evolved to recognize microbial infection and to respond to danger signals that appear under disease conditions. The most recently described innate immune receptor family is the Nod-like receptor (NLR) family. The inflammatory cytokines IL-1b and IL-18 are released only upon cleavage by the inflammatory caspase-1. Caspase-1 activity itself is controlled by a cytosolic signaling complex consisting of the NLR member NALP3 and the adapter protein ASC. After activation NALP3, ASC and caspase-1 form a multi-molecular complex termed the NALP3 inflammasome. The NALP3 inflammasome is activated in response to various membrane active bacterial toxins (e.g. nigericin, maitotoxin or gramicidin) or by incubation with crystalline materials (e.g. silica, asbestos, monosodium urate or alum). The mechanisms by which the NALP3 inflammasome is activated by physico-chemical diverse activators are not well understood. We demonstrate that crystals activate the NALP3 inflammasome in a process that requires phagocytosis and crystal uptake leads to lysosomal damage and rupture. Furthermore, sterile lysosomal damage is also sufficient to induce NALP3 activation and inhibition of phagosomal acidification or inhibition or lack of cathepsins impairs NALP3 activation. These results indicate that the NALP3 inflammasome can sense lysosomal damage induced by various means as an endogenous danger signal. Our results demonstrate a novel strategy of immune cells to recognize different classes of stimuli by a common, indirect mechanism. Cytosolic DNA can activate a NALP3 independent yet ASC dependent inflammasome. AIM2, a member of the PYHIN protein family, has a pyrin domain and a HIN200 DNA binding domain. We discovered that AIM2 binds to dsDNA and forms an inflammasome with ASC leading to caspase 1 activation. These pathways are promising new targets for pharmacological inhibitors with broad clinical significance. Disclosures No relevant conflicts of interest to declare.
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Chou, Wei-Chun, Elena Rampanelli, Xin Li, and Jenny P. Y. Ting. "Impact of intracellular innate immune receptors on immunometabolism." Cellular & Molecular Immunology 19, no. 3 (October 25, 2021): 337–51. http://dx.doi.org/10.1038/s41423-021-00780-y.
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AbstractImmunometabolism, which is the metabolic reprogramming of anaerobic glycolysis, oxidative phosphorylation, and metabolite synthesis upon immune cell activation, has gained importance as a regulator of the homeostasis, activation, proliferation, and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity. Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection, inflammation, cancer, autoimmune diseases, and metabolic disorders. The crosstalk between the PI3K–AKT–mTOR and LKB1–AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism. The bidirectional interaction between immune cells and metabolism is a topic of intense study. Toll-like receptors (TLRs), cytokine receptors, and T and B cell receptors have been shown to activate multiple downstream metabolic pathways. However, how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood. The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors, such as nucleotide-binding and leucine-rich repeat-containing receptors (NLRs, or NOD-like receptors), absent in melanoma 2 (AIM2)-like receptors (ALRs), and the cyclic dinucleotide receptor stimulator of interferon genes (STING). We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways. Whenever appropriate, this review will provide a brief contextual connection to pathogenic infections, autoimmune diseases, cancers, metabolic disorders, and/or inflammatory bowel diseases.
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Próchnicki, Tomasz, Matthew S. Mangan, and Eicke Latz. "Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation." F1000Research 5 (June 22, 2016): 1469. http://dx.doi.org/10.12688/f1000research.8614.1.
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Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns. These complexes enable activation of an inflammatory protease caspase-1, leading to a cell death process called pyroptosis and to proteolytic cleavage and release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Along with caspase-1, inflammasome components include an adaptor protein, ASC, and a sensor protein, which triggers the inflammasome assembly in response to a danger signal. The inflammasome sensor proteins are pattern recognition receptors belonging either to the NOD-like receptor (NLR) or to the AIM2-like receptor family. While the molecular agonists that induce inflammasome formation by AIM2 and by several other NLRs have been identified, it is not well understood how the NLR family member NLRP3 is activated. Given that NLRP3 activation is relevant to a range of human pathological conditions, significant attempts are being made to elucidate the molecular mechanism of this process. In this review, we summarize the current knowledge on the molecular events that lead to activation of the NLRP3 inflammasome in response to a range of K+ efflux-inducing danger signals. We also comment on the reported involvement of cytosolic Ca2+ fluxes on NLRP3 activation. We outline the recent advances in research on the physiological and pharmacological mechanisms of regulation of NLRP3 responses, and we point to several open questions regarding the current model of NLRP3 activation.
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Chiarini, Anna, Ubaldo Armato, Peng Hu, and Ilaria Dal Prà. "Danger-Sensing/Patten Recognition Receptors and Neuroinflammation in Alzheimer’s Disease." International Journal of Molecular Sciences 21, no. 23 (November 27, 2020): 9036. http://dx.doi.org/10.3390/ijms21239036.
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Fibrillar aggregates and soluble oligomers of both Amyloid-β peptides (Aβs) and hyperphosphorylated Tau proteins (p-Tau-es), as well as a chronic neuroinflammation are the main drivers causing progressive neuronal losses and dementia in Alzheimer’s disease (AD). However, the underlying pathogenetic mechanisms are still much disputed. Several endogenous neurotoxic ligands, including Aβs, and/or p-Tau-es activate innate immunity-related danger-sensing/pattern recognition receptors (PPRs) thereby advancing AD’s neuroinflammation and progression. The major PRR families involved include scavenger, Toll-like, NOD-like, AIM2-like, RIG-like, and CLEC-2 receptors, plus the calcium-sensing receptor (CaSR). This quite intricate picture stresses the need to identify the pathogenetically topmost Aβ-activated PRR, whose signaling would trigger AD’s three main drivers and their intra-brain spread. In theory, the candidate might belong to any PRR family. However, results of preclinical studies using in vitro nontumorigenic human cortical neurons and astrocytes and in vivo AD-model animals have started converging on the CaSR as the pathogenetically upmost PRR candidate. In fact, the CaSR binds both Ca2+ and Aβs and promotes the spread of both Ca2+ dyshomeostasis and AD’s three main drivers, causing a progressive neurons’ death. Since CaSR’s negative allosteric modulators block all these effects, CaSR’s candidacy for topmost pathogenetic PRR has assumed a growing therapeutic potential worth clinical testing.
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Kurt-Jones, Evelyn, Roy Soberman, Christine Vaine, Christopher Mackay, Glennice Ryan, and David Knipe. "Loss of the ITAM receptor CD200R1 attenuates HSV-1 infection and encephalitis. (68.15)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 68.15. http://dx.doi.org/10.4049/jimmunol.188.supp.68.15.
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Abstract We have discovered a novel role for the Immunoreceptor tyrosine-based activation motif (ITAM) containing receptor CD200R1 in virus infection. The host response to viral pathogens is driven by the activation of innate immune receptors that are triggered by pathogen-associated molecular pattern (PAMPs). These receptors include the transmembrane Toll-like receptors as well as the intracellular nucleic acid sensors RIG-I, Mda5, AIM2 and IFI16. ITAM receptors are known to both attenuate and activate signaling by innate receptors like TLRs but little is known about the potential impact of ITAMs on the outcome of viral infection. We generated CD200R1 knockout (KO) mice and infected with herpes simplex virus (HSV)-1. CD200R1 KO mice were protected from lethal HSV-1 encephalitis with >75% of the CD200R1 KOs surviving compared to 25% of the wild type (WT) mice, i.e., loss of CD200R1 conferred a survival advantage. This was not due to any obvious effects on the inflammatory response to infection. CD200R1 KO and WT mice had equivalent cytokine responses and leukocyte infiltration during the initial infection. Remarkably, HSV-1 virus replication was attenuated in CD200R1 KOs. Thus 50% of the CD200R1 KOs had cleared the virus from their brain by day 3-4 post-infection. In contrast, HSV-1 continued to replicate in the brains of 100% of the WT mice. Infection of cultured cells confirmed that CD200R1 expressing WT cells were more permissive for HSV-1 infection than CD200R1 KO cells.
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Lang, Yue, Fengna Chu, Donghui Shen, Weiguanliu Zhang, Chao Zheng, Jie Zhu, and Li Cui. "Role of Inflammasomes in Neuroimmune and Neurodegenerative Diseases: A Systematic Review." Mediators of Inflammation 2018 (2018): 1–11. http://dx.doi.org/10.1155/2018/1549549.
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Inflammasomes are multiprotein complexes that can sense pathogen-associated molecular patterns and damage-associated molecular signals. They are involved in the initiation and development of inflammation via activation of IL-1β and IL-18. Many recent studies suggest a strong correlation between inflammasomes and neurological diseases, such as multiple sclerosis (MS), Alzheimer’s disease (AD), and Parkinson’s disease (PD). Several components of inflammasomes, such as nucleotide-binding oligomerization domain- (NOD-) like receptor, absent in melanoma 2- (AIM2-) like receptors (ALRs), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1, as well as the upstream factors and downstream effectors, are associated with the initiation and development of MS and its animal model, experimental autoimmune encephalomyelitis. Additionally, inflammasomes affect the efficacy of interferon-β therapy in patients with MS. Finally, the strong association of inflammasomes with AD and PD needs to be further studied. In this review of latest literatures, we comprehensively tease out diverse roles of different kinds of inflammasomes in neuroimmune and neurodegenerative diseases, especially in the perspective of double roles involved in pathogenesis, and identify future research priorities.
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Cao, Xinyu, and Jia Xu. "Insights into inflammasome and its research advances in cancer." Tumori Journal 105, no. 6 (August 13, 2019): 456–64. http://dx.doi.org/10.1177/0300891619868007.
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Inflammation has long been proven to engage in tumor initiation and progression. Inflammasome, as a member of innate immunity-induced host defense inflammation, also plays critical roles in cancer. Inflammasome is a multiprotein complex responding to pathogen-associated molecular patterns and damage-associated molecular patterns. It is composed of receptors such as NOD-like receptors and AIM2-like receptors, adaptor protein ASC, and effector caspase-1, which can process proinflammatory cytokines interleukin (IL)–1β and IL-18. It has been reported that upregulated inflammasome activity is correlated to various types of cancers including breast cancer, gastric cancer, brain tumor, and malignant prostate, while inflammasomes also have a protective role in colitis-associated cancer. Autophagy, an intracellular recycling process for maintaining homeostasis, is deemed to contribute to the underlying mechanism of its dual roles in cancer. It has been found that distinct tumor stages and different isotypes of caspases involved in the inflammasome pathway can affect the roles of inflammasome in cancer. In this review, we update the latest evidence of inflammasome roles in cancer and novel inflammasome pathway-targeting agents for immunotherapy and discuss future research directions of inflammasome-based target therapy.
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Stehlik, Christian, Sonal Khare, Rojo Ratsimandresy, Lúcia de Almeida, Carla Cuda, Stephanie Rellick, Alexander Misharin, et al. "POP3 is a novel inhibitor of ALR inflammasomes and controls host defense to DNA virus infections (INM6P.411)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 122.8. http://dx.doi.org/10.4049/jimmunol.192.supp.122.8.
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Abstract The innate immune system responds to infections and tissue damage by activating cytosolic sensory complexes called inflammasomes. Cytosolic DNA is sensed by AIM2-like receptors (ALRs) during bacterial and viral infections and in autoimmune diseases. Subsequently, recruitment of the adaptor protein ASC through PYRIN domain (PYD)-PYD interaction, links ALRs to the activation of caspase-1 and subsequent maturation of the proinflammatory cytokines IL-1β IL-18 and induction of pyroptotic cell death. A controlled inflammasome response is crucial for maintaining homeostasis, whereas excessive and uncontrolled cytokine production contributes to autoinflammatory diseases. However, ALR inflammasome regulation is poorly understood. Here, we identified the type I interferon (IFN)-inducible PYD-only protein 3 (POP3) as a binding partner of ALRs. POP3 competes with ASC for recruitment to ALRs and thereby inhibits DNA virus-induced ALR inflammasome activation and IL-18 and IFN-γ-dependent host defense in vivo. A mouse model with macrophage-specific POP3 expression recapitulates global AIM2 deficiency and thus, emphasizes the importance of ALR inflammasome regulation in the monocytic/macrophage lineage. Collectively, we show that POP3 represents one of the type I IFN response factors that regulate human and mouse ALR inflammasomes in macrophages within a type I IFN-regulatory loop.
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Wu, Yung-Hsuan, Wen-Chi Kuo, and Ming-Zong Lai. "Participation of c-FLIP in NLRP3 and AIM2 inflammasome activation (IRC5P.453)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 125.2. http://dx.doi.org/10.4049/jimmunol.192.supp.125.2.
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Abstract Cellular FLICE-inhibitory protein (c-FLIP) is an inhibitor of caspase-8 and is required for macrophage survival. Recent studies have revealed a selective role of caspase-8 in noncanonical IL-1b production that is independent of caspase-1 or inflammasome. Here we demonstrated that c-FLIPL is an unexpected contributor to canonical inflammasome activation for the generation of caspase-1 and active IL-1b. Hemizygotic deletion of c-FLIP impaired ATP- and monosodium uric acid (MSU)-induced IL-1b production in macrophages primed through Toll-like receptors (TLRs). Decreased IL-1b expression was attributed to a reduced activation of caspase-1 in c-FLIP hemizygotic cells. In contrast, the production of TNF-a was not affected by downregulation in c-FLIP. c-FLIPL interacted with NLRP3 or procaspase-1. c-FLIP is required for the full NLRP3 inflammasome assembly, and c-FLIP is associated with NLRP3 inflammasome. c-FLIP downregulation also reduced AIM2 inflammasome activation. In contrast, c-FLIP inhibited SMAC mimetic-, FasL-, or Dectin-1-induced IL-1b generation that is caspase-8-mediated. Our results demonstrate a prominent role of c-FLIPL in the optimal activation of the NLRP3 and AIM2 inflammasomes, and suggest that c-FLIP could be a valid target for treatment of inflammatory diseases caused by overactivation of inflammasomes.
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Briard, Benoit, David E. Place, and Thirumala-Devi Kanneganti. "DNA Sensing in the Innate Immune Response." Physiology 35, no. 2 (March 1, 2020): 112–24. http://dx.doi.org/10.1152/physiol.00022.2019.
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The innate immune system recognizes conserved pathogen-associated molecular patterns and produces inflammatory cytokines that direct downstream immune responses. The inappropriate localization of DNA within the cell cytosol or endosomal compartments indicates that a cell may either be infected by a DNA virus or bacterium, or has problems with its own nuclear integrity. This DNA is sensed by certain receptors that mediate cytokine production and, in some cases, initiate an inflammatory and lytic form of cell death called pyroptosis. Dysregulation of these DNA-sensing pathways is thought to contribute to autoimmune diseases and the development of cancer. In this review, we will discuss the DNA sensors Toll-like receptor 9 (TLR9), cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), absent in melanoma 2 (AIM2), and interferon gamma-inducible 16 (IFI16), their ligands, and their physiological significance. We will also examine the less-well-understood DEAH- and DEAD-box helicases DHX9, DHX36, DDX41, and RNA polymerase III, each of which may play an important role in DNA-mediated innate immunity.
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Leichtle, Anke, Michelle Hernandez, Jasmine Lee, Kwang Pak, Nicholas J. Webster, Barbara Wollenberg, Stephen I. Wasserman, and Allen F. Ryan. "The role of DNA sensing and innate immune receptor TLR9 in otitis media." Innate Immunity 18, no. 1 (January 14, 2011): 3–13. http://dx.doi.org/10.1177/1753425910393539.
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Otitis media (OM), a common infectious disease in children, is associated with bacterial middle ear (ME) infection. Toll-like receptors (TLRs) are important mediators of innate immune responses, and TLR9 specifically recognizes the unmethylated cytidine-phosphate-guanosine (CpG) motifs in bacterial DNA. Additional sensors of foreign DNA have recently been identified. The role of DNA sensing and TLR9 was investigated in a murine model of OM induced by non-typeable Haemophilus influenzae (NTHi). Expression of genes related to DNA-sensing pathways involved in innate immunity was assessed via DNA microarray, qPCR and immunohistochemistry. Middle ear responses to NTHi were examined in wild-type and TLR9−/− mice by histopathology and bacterial culture. Expression of TLR9 signaling genes was modestly up-regulated during OM, as was TLR9 protein in both ME mucosal cells and infiltrating leukocytes. However, genes known to be regulated by CpG DNA were dramatically up-regulated, as were genes involved in DNA sensing by DIA, Pol-III and AIM2. Toll-like receptor 9 deletion significantly prolonged the inflammatory response induced by NTHi in the ME and delayed bacterial clearance. The results suggest that DNA sensing via TLR9 plays a role in OM pathogenesis and recovery. Alternative forms of DNA sensing may also contribute to OM.
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Jangra, Sonia, Kit-San Yuen, Michael George Botelho, and Dong-Yan Jin. "Epstein–Barr Virus and Innate Immunity: Friends or Foes?" Microorganisms 7, no. 6 (June 24, 2019): 183. http://dx.doi.org/10.3390/microorganisms7060183.
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Epstein–Barr virus (EBV) successfully persists in the vast majority of adults but causes lymphoid and epithelial malignancies in a small fraction of latently infected individuals. Innate immunity is the first-line antiviral defense, which EBV has to evade in favor of its own replication and infection. EBV uses multiple strategies to perturb innate immune signaling pathways activated by Toll-like, RIG-I-like, NOD-like, and AIM2-like receptors as well as cyclic GMP-AMP synthase. EBV also counteracts interferon production and signaling, including TBK1-IRF3 and JAK-STAT pathways. However, activation of innate immunity also triggers pro-inflammatory response and proteolytic cleavage of caspases, both of which exhibit proviral activity under some circumstances. Pathogenic inflammation also contributes to EBV oncogenesis. EBV activates NFκB signaling and induces pro-inflammatory cytokines. Through differential modulation of the proviral and antiviral roles of caspases and other host factors at different stages of infection, EBV usurps cellular programs for death and inflammation to its own benefits. The outcome of EBV infection is governed by a delicate interplay between innate immunity and EBV. A better understanding of this interplay will instruct prevention and intervention of EBV-associated cancers.
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Monteith, Andrew J., SunAh Kang, Eric Scott, Kai Hillman, Zenon Rajfur, Ken Jacobson, M. Joseph Costello, and Barbara J. Vilen. "Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus." Proceedings of the National Academy of Sciences 113, no. 15 (March 28, 2016): E2142—E2151. http://dx.doi.org/10.1073/pnas.1513943113.
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Defects in clearing apoptotic debris disrupt tissue and immunological homeostasis, leading to autoimmune and inflammatory diseases. Herein, we report that macrophages from lupus-prone MRL/lpr mice have impaired lysosomal maturation, resulting in heightened ROS production and attenuated lysosomal acidification. Impaired lysosomal maturation diminishes the ability of lysosomes to degrade apoptotic debris contained within IgG–immune complexes (IgG-ICs) and promotes recycling and the accumulation of nuclear self-antigens at the membrane 72 h after internalization. Diminished degradation of IgG-ICs prolongs the intracellular residency of nucleic acids, leading to the activation of Toll-like receptors. It also promotes phagosomal membrane permeabilization, allowing dsDNA and IgG to leak into the cytosol and activate AIM2 and TRIM21. Collectively, these events promote the accumulation of nuclear antigens and activate innate sensors that drive IFNα production and heightened cell death. These data identify a previously unidentified defect in lysosomal maturation that provides a mechanism for the chronic activation of intracellular innate sensors in systemic lupus erythematosus.
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Proell, Martina, Motti Gerlic, Peter D. Mace, John C. Reed, and Stefan J. Riedl. "The CARD plays a critical role in ASC foci formation and inflammasome signalling." Biochemical Journal 449, no. 3 (January 9, 2013): 613–21. http://dx.doi.org/10.1042/bj20121198.
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The ASC (apoptosis speck-like protein) is a key component of multimeric protein complexes that mediate inflammation and host defence. Comprising a PYD (Pyrin) domain and a CARD (caspase activation and recruitment domain), ASC functions downstream of NLRs (nucleotide-binding domain, leucine-rich repeat-containing receptors) and AIM2 (absent in melanoma 2) through the formation of supramolecular structures termed inflammasomes. However, the mechanism underlying ASC signalling and its dependency on oligomeric arrangements in inflammasome formation remain poorly understood. When expressed in cells, ASC forms discrete foci (called ‘specks’) typically with one speck per cell. We employed a BiFC (bimolecular fluorescence complementation) system to investigate and visualize ASC foci formation in living cells. We demonstrated that the CARD of ASC plays a central role in ASC inflammasome assembly, representing the minimal unit capable of forming foci in conjunction with the caspase 1 CARD. Mutational studies point to multiple surfaces on the ASC CARD and two predominant areas on the caspase 1 CARD mediating the formation of ASC/caspase 1 foci. The lack of foci formation for ASC CARD mutants correlates with a loss of IL-1β (interleukin 1β) processing in response to NLRP (NLR family, PYD domain-containing) 3 or AIM2 agonists in RAW264.7 cell reconstitution assays. Analogously, we show that productive formation of the Salmonella typhimurium-induced NLRC4 (NLR family CARD domain-containing protein 4) inflammasome is dependent on ASC–CARD-mediated platform formation. Thus the results of the present study depict a central role of CARDs in the formation of ASC signalling platforms and provide an important tool for investigation of CARD-dependent networks.
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LI, He, Zhi-Xin WANG, and Jia-Wei WU. "Comparative Purification and Characterization of Two HIN Domains, Hematopoietic Interferon-Inducible Nuclear Antigens with a 200-Amino-Acid Repeat, in Murine AIM2-Like Receptors." Bioscience, Biotechnology, and Biochemistry 77, no. 11 (November 23, 2013): 2283–87. http://dx.doi.org/10.1271/bbb.130544.
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Sun, Zhezhe, Mark Nyanzu, Su Yang, Xiaohong Zhu, Kankai Wang, Junnan Ru, Enxing Yu, et al. "VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice." Oxidative Medicine and Cellular Longevity 2020 (April 15, 2020): 1–21. http://dx.doi.org/10.1155/2020/7879629.
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Background. Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods. Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results. We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion. In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.
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Ontiveros, Carlos Oscar, Eusondia Arnett, and Larry S. Schlesinger. "Characterization of AIM2 expression in human macrophages during M. tuberculosis infection." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 62.11. http://dx.doi.org/10.4049/jimmunol.202.supp.62.11.
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Abstract Tuberculosis (TB) is a leading contributor to global mortality and is a well-known threat to global health. The disease-causing bacterium, Mycobacterium tuberculosis (M.tb), has demonstrated resistance to current treatments, thus necessitating novel methods to fight the disease. The investigation of host-bacterium interactions may provide insight for development of effective host-directed therapies, thus circumventing antibiotic resistance. The body’s defense system against airborne M.tb includes alveolar macrophages (AMs) responsible for elimination of foreign agents. However, they do not effectively eliminate M.tb, leading to bacterial propagation. It was previously found that the NOD-like receptor, absent in melanoma 2 (AIM2), plays key roles in M.tb infection in murine macrophages. However, the expression of AIM2 in primary human cells during M.tb infection remains unknown. To this end, we characterized AIM2 expression in human monocyte-derived macrophages (MDMs) and AMs during M.tb infection via quantitative real-time PCR (qRT-PCR). We found that M.tb induces AIM2 transcripts in human MDMs and AMs, in a time-dependent manner. We also investigated the contribution of peroxisome proliferator-activated receptor (PPAR)γ to AIM2 expression due to its known regulation of several genes involved in the human macrophage response to M.tb. We found that PPARγ mediates AIM2 expression. In conclusion, the increased AIM2 gene expression observed in MDMs and AMs during M.tb infection necessitates further investigation into its function and its potential use as a target for M.tb host-directed therapy.
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Wu, Yong, Huan Yang, Sujuan Xu, Ming Cheng, Jie Gu, Weichen Zhang, Shaojun Liu, and Minmin Zhang. "AIM2 inflammasome contributes to aldosterone-induced renal injury via endoplasmic reticulum stress." Clinical Science 136, no. 1 (January 2022): 103–20. http://dx.doi.org/10.1042/cs20211075.
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Abstract Inflammatory response and renal fibrosis are the hallmarks of chronic kidney disease (CKD). However, the specific mechanism of aldosterone-induced renal injury in the progress of CKD requires elucidation. Emerging evidence has demonstrated that absent in melanoma 2 (AIM2)-mediated inflammasome activation and endoplasmic reticulum stress (ERS) play a pivotal role in the renal fibrosis. Here, we investigated whether overexpression or deficiency of AIM2 affects ERS and fibrosis in aldosterone-infused renal injury. Interestingly, we found that AIM2 was markedly expressed in the diseased proximal tubules from human and experimental CKD. Mechanically, overactivation of AIM2 aggravated aldosterone-induced ERS and fibrotic changes in vitro while knockdown of AIM2 blunted these effects in vivo and in vitro. By contrast, AIM2 deficiency ameliorated renal structure and function deterioration, decreased proteinuria levels and lowered systolic blood pressure in vivo; silencing of AIM2 blocked inflammasome-mediated signaling pathway, relieved ERS and fibrotic changes in vivo. Furthermore, mineralocorticoid receptor (MR) antagonist eplerenone and ERS inhibitor tauroursodeoxycholic acid (TUDCA) had nephroprotective effects on the basis of AIM2 overactivation in vitro, while they failed to produce a more remarkable renoprotective effect on the treatment of AIM2 silence in vitro. Notably, the combination of TUDCA with AIM2 knockdown significantly reduced proteinuria levels in vivo. Additionally, immunofluorescence assay identified that apoptosis-associated speck-like protein (ASC) recruitment and Gasdermin-D (GSDMD) cleavage respectively occurred in the glomeruli and tubules in vivo. These findings establish a crucial role for AIM2 inflammasome in aldosterone-induced renal injury, which may provide a novel therapeutic target for the pathogenesis of CKD.
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Tupik, Juselyn D., Justin W. Markov Madanick, Hannah M. Ivester, and Irving C. Allen. "Detecting DNA: An Overview of DNA Recognition by Inflammasomes and Protection against Bacterial Respiratory Infections." Cells 11, no. 10 (May 19, 2022): 1681. http://dx.doi.org/10.3390/cells11101681.
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The innate immune system plays a key role in modulating host immune defense during bacterial disease. Upon sensing pathogen-associated molecular patterns (PAMPs), the multi-protein complex known as the inflammasome serves a protective role against bacteria burden through facilitating pathogen clearance and bacteria lysis. This can occur through two mechanisms: (1) the cleavage of pro-inflammatory cytokines IL-1β/IL-18 and (2) the initiation of inflammatory cell death termed pyroptosis. In recent literature, AIM2-like Receptor (ALR) and Nod-like Receptor (NLR) inflammasome activation has been implicated in host protection following recognition of bacterial DNA. Here, we review current literature synthesizing mechanisms of DNA recognition by inflammasomes during bacterial respiratory disease. This process can occur through direct sensing of DNA or indirectly by sensing pathogen-associated intracellular changes. Additionally, DNA recognition may be assisted through inflammasome–inflammasome interactions, specifically non-canonical inflammasome activation of NLRP3, and crosstalk with the interferon-inducible DNA sensors Stimulator of Interferon Genes (STING) and Z-DNA Binding Protein-1 (ZBP1). Ultimately, bacterial DNA sensing by inflammasomes is highly protective during respiratory disease, emphasizing the importance of inflammasome involvement in the respiratory tract.
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Waller, Tobias, Laura Kesper, Josefine Hirschfeld, Henrik Dommisch, Johanna Kölpin, Johannes Oldenburg, Julia Uebele, et al. "Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner." Infection and Immunity 84, no. 4 (February 8, 2016): 1194–204. http://dx.doi.org/10.1128/iai.01390-15.
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Porphyromonas gingivalisis an important member of the anaerobic oral flora. Its presence fosters growth of periodontal biofilm and development of periodontitis. In this study, we demonstrated that lipophilic outer membrane vesicles (OMV) shed fromP. gingivalispromote monocyte unresponsiveness to liveP. gingivalisbut retain reactivity to stimulation with bacterial DNA isolated fromP. gingivalisor AIM2 ligand poly(dA·dT). OMV-mediated tolerance ofP. gingivalisis characterized by selective abrogation of tumor necrosis factor (TNF). Neutralization of interleukin-10 (IL-10) during OMV challenge partially restores monocyte responsiveness toP. gingivalis; full reactivity toP. gingivaliscan be restored by inhibition of mTOR signaling, which we previously identified as the major signaling pathway promoting Toll-like receptor 2 and Toll-like receptor 4 (TLR2/4)-mediated tolerance in monocytes. However, despite previous reports emphasizing a central role of TLR2 in innate immune recognition ofP. gingivalis, our current findings highlight a selective role of TLR4 in the promotion of OMV-mediated TNF tolerance: only blockade of TLR4—and not of TLR2—restores responsiveness toP. gingivalis. Of further note, OMV-mediated tolerance is preserved in the presence of cytochalasin B and chloroquine, indicating that triggering of surface TLR4 is sufficient for this effect. Taking the results together, we propose thatP. gingivalisOMV contribute to local immune evasion ofP. gingivalisby hampering the host response.
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Gopinathan, Unni, Reidun Øvstebø, Ole Kristoffer Olstad, Berit Brusletto, Hans Christian Dalsbotten Aass, Peter Kierulf, Petter Brandtzaeg, and Jens Petter Berg. "Global Effect of Interleukin-10 on the Transcriptional Profile Induced by Neisseria meningitidis in Human Monocytes." Infection and Immunity 80, no. 11 (September 10, 2012): 4046–54. http://dx.doi.org/10.1128/iai.00386-12.
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ABSTRACTIn meningococcal septic shock, the dominant inducer of inflammation is lipopolysaccharide (LPS) in the outer membrane ofNeisseria meningitidis, while interleukin-10 (IL-10) is the principal anti-inflammatory cytokine. We have used microarrays and Ingenuity Pathway Analysis to study the global effects of IL-10 on gene expression induced byN. meningitidis, after exposure of human monocytes (n= 5) for 3 h toN. meningitidis(106cells/ml), recombinant human IL-10 (rhIL-10) (25 ng/ml), andN. meningitidiscombined with rhIL-10.N. meningitidisand IL-10 differentially expressed 3,579 and 648 genes, respectively. IL-10 downregulated 125 genes which were upregulated byN. meningitidis, including NLRP3, the key molecule of the NLRP3 inflammasome. IL-10 also upregulated 270 genes which were downregulated byN. meningitidis, including members of the leukocyte immunuglobulin-like receptor (LIR) family. Fifty-three genes revealed a synergistically increased expression whenN. meningitidisand IL-10 were combined. AIM2 (the principal molecule of the AIM2 inflammasome) was among these genes (fold change [FC], 18.3 versus 7.4 and 9.4 after stimulation byN. meningitidisand IL-10, respectively). We detected reduced concentrations (92% to 40%) of six cytokines (IL-1b, IL-6, IL-8, tumor necrosis factor alpha [TNF-α], macrophage inflammatory protein alpha [MIP-α], MIP-β) in the presence of IL-10, compared with concentrations with stimulation byN. meningitidisalone. Our data analysis of the effects of IL-10 on gene expression induced byN. meningitidissuggests that high plasma levels of IL-10 in meningococcal septic shock plasma may have a profound effect on a variety of functions and cellular processes in human monocytes, including cell-to-cell signaling, cellular movement, cellular development, antigen presentation, and cell death.
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Deng, Meng, Haitao Guo, Jason W. Tam, Brandon M. Johnson, W. June Brickey, James S. New, Austin Lenox, et al. "Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR." Journal of Experimental Medicine 216, no. 12 (October 26, 2019): 2838–53. http://dx.doi.org/10.1084/jem.20190111.
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The role of lipids in inflammasome activation remains underappreciated. The phospholipid, platelet-activating factor (PAF), exerts multiple physiological functions by binding to a G protein–coupled seven-transmembrane receptor (PAFR). PAF is associated with a number of inflammatory disorders, yet the molecular mechanism underlying its proinflammatory function remains to be fully elucidated. We show that multiple PAF isoforms and PAF-like lipids can activate the inflammasome, resulting in IL-1β and IL-18 maturation. This is dependent on NLRP3, ASC, caspase-1, and NEK7, but not on NLRC4, NLRP1, NLRP6, AIM2, caspase-11, or GSDMD. Inflammasome activation by PAF also requires potassium efflux and calcium influx but not lysosomal cathepsin or mitochondrial reactive oxygen species. PAF exacerbates peritonitis partly through inflammasome activation, but PAFR is dispensable for PAF-induced inflammasome activation in vivo or in vitro. These findings reveal that PAF represents a damage-associated signal that activates the canonical inflammasome independently of PAFR and provides an explanation for the ineffectiveness of PAFR antagonist in blocking PAF-mediated inflammation in the clinic.
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Lee, Eun Hye, Jin Hak Shin, Seon Sook Kim, and Su Ryeon Seo. "Sinapic Acid Controls Inflammation by Suppressing NLRP3 Inflammasome Activation." Cells 10, no. 9 (September 6, 2021): 2327. http://dx.doi.org/10.3390/cells10092327.
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A natural phenolic acid compound, sinapic acid (SA), is a cinnamic acid derivative that contains 3,5-dimethoxyl and 4-hydroxyl substitutions in the phenyl ring of cinnamic acid. SA is present in various orally edible natural herbs and cereals and is reported to have antioxidant, antitumor, anti-inflammatory, antibacterial, and neuroprotective activities. Although the anti-inflammatory function of SA has been reported, the effect of SA on the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome has not been explored. In the present study, to elucidate the anti-inflammatory mechanism of SA, we examined whether SA modulates the NLRP3 inflammasome. We found that SA blocked caspase-1 activation and IL-1β secretion by inhibiting NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs). Apoptosis-associated speck-like protein containing CARD (ASC) pyroptosome formation was consistently blocked by SA treatment. SA specifically inhibited NLRP3 activation but not the NLRC4 or AIM2 inflammasomes. In addition, SA had no significant effect on the priming phase of the NLRP3 inflammasome, such as pro-IL-1β and NLRP3 inflammasome expression levels. Moreover, we found that SA attenuated IL-1β secretion in LPS-induced systemic inflammation in mice and reduced lethality from endotoxic shock. Our findings suggest that the natural compound SA has potential therapeutic value for the suppression of NLRP3 inflammasome-associated inflammatory diseases.
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Poli, Giulia, Consuelo Fabi, Marina Maria Bellet, Claudio Costantini, Luisa Nunziangeli, Luigina Romani, and Stefano Brancorsini. "Epigenetic Mechanisms of Inflammasome Regulation." International Journal of Molecular Sciences 21, no. 16 (August 11, 2020): 5758. http://dx.doi.org/10.3390/ijms21165758.
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The innate immune system represents the host’s first-line defense against pathogens, dead cells or environmental factors. One of the most important inflammatory pathways is represented by the activation of the NOD-like receptor (NLR) protein family. Some NLRs induce the assembly of large caspase-1-activating complexes called inflammasomes. Different types of inflammasomes have been identified that can respond to distinct bacterial, viral or fungal infections; sterile cell damage or other stressors, such as metabolic imbalances. Epigenetic regulation has been recently suggested to provide a complementary mechanism to control inflammasome activity. This regulation can be exerted through at least three main mechanisms, including CpG DNA methylation, histones post-translational modifications and noncoding RNA expression. The repression or promotion of expression of different inflammasomes (NLRP1, NLRP2, NLRP3, NLRP4, NLRP6, NLRP7, NLRP12 and AIM2) through epigenetic mechanisms determines the development of pathologies with variable severity. For example, our team recently explored the role of microRNAs (miRNAs) targeting and modulating the components of the inflammasome as potential biomarkers in bladder cancer and during therapy. This suggests that the epigenetic control of inflammasome-related genes could represent a potential target for further investigations of molecular mechanisms regulating inflammatory pathways.
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Prasad, Amit, Zaida Ramirez-Ortiz, and Terry Means. "Mechanisms of AIM2 inflammasome regulation (P4093)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 127.18. http://dx.doi.org/10.4049/jimmunol.190.supp.127.18.
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Abstract Systemic lupus erythematosus (SLE) is an autoimmune syndrome typified by autoantibodies against DNA, chromatin, and RNA-associated proteins. Experimental evidence from our group and others suggests that RNA- and DNA-containing immune complexes isolated from SLE patients activates dendritic cells (DCs) through the nucleic acid sensors TLR7 and TLR9, respectively. Using a highly parallel shRNA pooled screening strategy; we identified several additional genes that positively regulate innate responses to stimulatory RNA and DNA complexes that contribute to SLE pathology. Here we show that triggering receptor expressed on myeloid cells like 4 (Treml4) regulates innate sensing of dsDNA and ssRNA in macrophages and DCs. To validate these findings we generated TREML4-deficient mice. We found that dsDNA or ssRNA stimulation of DCs isolated from TREML4-deficient mice produced significantly less IL-1 beta compared to wild-type DCs. We also observed lower caspase-1 and pro-inflammatory cytokines in Treml4 deficient DCs. In addition, AIM2 expression and function are significantly impaired in TREML4-deficient cells compared to wild-type cells. Our results suggest further study of this new signaling intermediate will give better insight into autoimmune diseases, such as SLE and may serve as a potential therapeutic target.
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Park, Eunjoo, Hee Sam Na, Yu-Ri Song, Seong Yeol Shin, You-Me Kim, and Jin Chung. "Activation of NLRP3 and AIM2 Inflammasomes by Porphyromonas gingivalis Infection." Infection and Immunity 82, no. 1 (October 14, 2013): 112–23. http://dx.doi.org/10.1128/iai.00862-13.
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ABSTRACTPorphyromonas gingivalis, a major periodontopathogen, is involved in the pathogenesis of periodontitis. Interleukin-1β (IL-1β), a proinflammatory cytokine, regulates innate immune responses and is critical for the host defense against bacterial infection. However, excessive IL-1β is linked to periodontal destruction. IL-1β synthesis, maturation, and secretion are tightly regulated by Toll-like receptor (TLR) signaling and inflammasome activation. We found much higher levels of inflammasome components in the gingival tissues from patients with chronic periodontitis than in those from healthy controls. To investigate the molecular mechanisms by whichP. gingivalisinfection causes IL-1β secretion, we examined the characteristics ofP. gingivalis-induced signaling in differentiated THP-1 cells. We found thatP. gingivalisinduces IL-1β secretion and inflammatory cell death via caspase-1 activation. We also found thatP. gingivalis-induced IL-1β secretion and pyroptic cell death required both NLRP3 and AIM2 inflammasome activation. The activation of the NLRP3 inflammasome was mediated by ATP release, the P2X7receptor, and lysosomal damage. In addition, we found that the priming signal via TLR2 and TLR4 activation precedesP. gingivalis-induced IL-1β release. Our study provides novel insight into the innate immune response againstP. gingivalisinfection which could potentially be used for the prevention and therapy of periodontitis.
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Jung, Sung-Soo, Jong-Seok Moon, Jin-Fu Xu, Emeka Ifedigbo, Stefan W. Ryter, Augustine M. K. Choi, and Kiichi Nakahira. "Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages." American Journal of Physiology-Lung Cellular and Molecular Physiology 308, no. 10 (May 15, 2015): L1058—L1067. http://dx.doi.org/10.1152/ajplung.00400.2014.
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Inflammasomes are cytosolic protein complexes that promote the cleavage of caspase-1, which leads to the maturation and secretion of proinflammatory cytokines, including interleukin-1β (IL-1β) and IL-18. Among the known inflammasomes, the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3)-dependent inflammasome is critically involved in the pathogenesis of various acute or chronic inflammatory diseases. Carbon monoxide (CO), a gaseous molecule physiologically produced in cells and tissues during heme catabolism, can act as an anti-inflammatory molecule and a potent negative regulator of Toll-like receptor signaling pathways. To date, the role of CO in inflammasome-mediated immune responses has not been fully investigated. Here, we demonstrated that CO inhibited caspase-1 activation and the secretion of IL-1β and IL-18 in response to lipopolysaccharide (LPS) and ATP treatment in bone marrow-derived macrophages. CO also inhibited IL-18 secretion in response to LPS and nigericin treatment, another NLRP3 inflammasome activation model. In contrast, CO did not suppress IL-18 secretion in response to LPS and poly(dA:dT), an absent in melanoma 2 (AIM2)-mediated inflammasome model. LPS and ATP stimulation induced the formation of complexes between NLRP3 and apoptosis-associated speck-like protein, or NLRP3 and caspase-1. CO treatment inhibited these molecular interactions that were induced by LPS and ATP. Furthermore, CO inhibited mitochondrial ROS generation and the decrease of mitochondrial membrane potential induced by LPS and ATP in macrophages. We also observed that the inhibitory effect of CO on the translocation of mitochondrial DNA into the cytosol was associated with suppression of cytokine secretion. Our results suggest that CO negatively regulates NLRP3 inflammasome activation by preventing mitochondrial dysfunction.
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Feria-Garzón, Manuel G., María T. Rugeles, Juan C. Hernandez, Jorge A. Lujan, and Natalia A. Taborda. "Sulfasalazine as an Immunomodulator of the Inflammatory Process during HIV-1 Infection." International Journal of Molecular Sciences 20, no. 18 (September 11, 2019): 4476. http://dx.doi.org/10.3390/ijms20184476.
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Background: HIV-1 induces an uncontrolled inflammatory response of several immune components, such as inflammasomes. These molecular complexes, associated with Toll-like receptor (TLR) activity, induce the maturation and release of IL-1β and IL-18 and eventually induce pyroptosis. It has been previously demonstrated that HIV induces inflammasome activation, which is significantly lower in the gastrointestinal tissue and blood from people living with HIV-1 with spontaneous control of viral replication. Therefore, immunomodulatory agents could be useful in improving HIV prognosis. Objective: To evaluate the potential inhibitory effect of sulfasalazine (SSZ) on inflammasomes and TLRs in peripheral blood mononuclear cells (PBMCs) from people living with HIV and healthy donors. Methods: PBMCs were obtained from 15 people living with HIV and 15 healthy donors. Cells were stimulated with agonists of TLRs and inflammasomes and subsequently treated with SSZ. The concentration of IL-1β and the relative expression of NLRP3, NLRC4, NLRP1, AIM2, ASC, Caspase-1, IL-1β, and IL-18 were quantified. Results: Cells treated with SSZ exhibited a decreased IL-1β production after inflammasome and TLR stimulation, as well as regulation of inflammasome-related genes, in both people with HIV and healthy individuals. The concentration of IL-1β was positively correlated with the CD4+ T-cell count and negatively with the viral load. Conclusion: Our results suggest that SSZ has an immunomodulatory effect on inflammasome and TLR activation that depends on the clinical HIV status.
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Ji, Jianjian, Jingjing Xu, Shuli Zhao, Fei Liu, Jingjing Qi, Yuxian Song, Jing Ren, Tingting Wang, Huan Dou, and Yayi Hou. "Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs." Clinical Science 130, no. 16 (July 7, 2016): 1453–67. http://dx.doi.org/10.1042/cs20160311.
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Although major advancements have made in investigating the aetiology of SLE (systemic lupus erythaematosus), the role of MDSCs (myeloid-derived suppressor cells) in SLE progression remains confused. Recently, some studies have revealed that MDSCs play an important role in lupus mice. However, the proportion and function of MDSCs in lupus mice and SLE patients are still poorly understood. In the present study, we investigated the proportion and function of MDSCs using different stages of MRL/lpr lupus mice and specimens from SLE patients with different activity. Results showed that splenic granulocytic (G-)MDSCs were significantly expanded by increasing the expression of CCR1 (CC chemokine receptor 1) in diseased MRL/lpr lupus mice and in high-disease-activity SLE patients. However, the proportion of monocytic (M-)MDSCs remains similar in MRL/lpr lupus mice and SLE patients. G-MDSCs produce high levels of ROS (reactive oxygen species) through increasing gp91phox expression, and activated TLR2 (Toll-like receptor 2) and AIM2 (absent in melanoma 2) inflammasome in M-MDSCs lead to IL-1β (interleukin 1β) expression in diseased MRL/lpr mice and high-disease-activity SLE patients. Previous study has revealed that MDSCs could alter the plasticity of Th17 (T helper 17) cells and Tregs (regulatory T-cells) via ROS and IL-1β. Co-culture experiments showed that G-MDSCs impaired Treg differentiation via ROS and M-MDSCs promoted Th17 cell polarization by IL-1β in vitro. Furthermore, adoptive transfer or antibody depletion of MDSCs in MRL/lpr mice confirmed that MDSCs influenced the imbalance of Tregs and Th17 cells in vivo. Our results indicate that MDSCs with the capacity to regulate Th17 cell/Treg balance may be a critical pathogenic factor in SLE.
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Finethy, Ryan, Ine Jorgensen, Arun K. Haldar, Marcel R. de Zoete, Till Strowig, Richard A. Flavell, Masahiro Yamamoto, Uma M. Nagarajan, Edward A. Miao, and Jörn Coers. "Guanylate Binding Proteins Enable Rapid Activation of Canonical and Noncanonical Inflammasomes in Chlamydia-Infected Macrophages." Infection and Immunity 83, no. 12 (September 28, 2015): 4740–49. http://dx.doi.org/10.1128/iai.00856-15.
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Interferon (IFN)-inducible guanylate binding proteins (GBPs) mediate cell-autonomous host resistance to bacterial pathogens and promote inflammasome activation. The prevailing model postulates that these two GBP-controlled activities are directly linked through GBP-dependent vacuolar lysis. It was proposed that the rupture of pathogen-containing vacuoles (PVs) by GBPs destroyed the microbial refuge and simultaneously contaminated the host cell cytosol with microbial activators of inflammasomes. Here, we demonstrate that GBP-mediated host resistance and GBP-mediated inflammatory responses can be uncoupled. We show that PVs formed by the rodent pathogenChlamydia muridarum, so-called inclusions, remain free of GBPs and thatC. muridarumis impervious to GBP-mediated restrictions on bacterial growth. Although GBPs neither bind toC. muridaruminclusions nor restrictC. muridarumgrowth, we find that GBPs promote inflammasome activation inC. muridarum-infected macrophages. We demonstrate thatC. muridaruminfections induce GBP-dependent pyroptosis through both caspase-11-dependent noncanonical and caspase-1-dependent canonical inflammasomes. Among canonical inflammasomes, we find thatC. muridarumand the human pathogenChlamydia trachomatisactivate not only NLRP3 but also AIM2. Our data show that GBPs support fast-kinetics processing and secretion of interleukin-1β (IL-1β) and IL-18 by the NLRP3 inflammasome but are dispensable for the secretion of the same cytokines at later times postinfection. Because IFN-γ fails to induce IL-1β transcription, GBP-dependent fast-kinetics inflammasome activation can drive the preferential processing of constitutively expressed IL-18 in IFN-γ-primed macrophages in the absence of prior Toll-like receptor stimulation. Together, our results reveal that GBPs control the kinetics of inflammasome activation and thereby shape macrophage responses toChlamydiainfections.
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Calderon, I., and R. Mina. "THU0010 GENES ASSOCIATED WITH NUCLEOTIDE OLIGOMERIZATION DOMAIN-LIKE RECEPTOR SIGNALING PATHWAY ARE UPREGULATED IN CUTANEOUS LUPUS ERYTHEMATOSUS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 217.3–217. http://dx.doi.org/10.1136/annrheumdis-2020-eular.6159.
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Background:Cutaneous Lupus Erythematosus (CLE) is a disfiguring autoimmune skin disorder with several subtypes: discoid lupus, subacute cutaneous lupus, and acute cutaneous lupus. CLE is associated with defects in the adaptive immune system, and, at times, systemic involvement. The innate immune system is likely involved as seen in the presence of interface dermatitis, which is observed in viral exanthems, and improvement of CLE using inhibitors to membrane-bound Pattern Recognition Receptors.Objectives:Compare the expression of genes associated with the innate immune system in active CLE skin lesions of different subtypes compared to normal skin controls.Methods:Five datasets selected from the Gene Expression Omnibus (GEO) were analyzed using GEO2R to compare the gene expressions between different subtypes of CLE. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, Gene Card, and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway analysis were used to identify the interaction and function of specific genes.Results:There were a total of 147 CLE skin samples and 52 normal controls. Genes associated with the Nucleotide-Binding Oligomerization Domain-Like Receptor (NLR) signaling pathway were upregulated in CLE skin samples (adjusted p-value < 0.001). Five genes associated with the NLR signaling pathway, STAT1, OAS1, OAS2, OAS3, and AIM2, were found to be upregulated in skin samples of CLE patients in all datasets, regardless of type, compared to normal controls in all datasets. These five genes are associated with transcription activation, regulation of viral infection, and interferon response.Conclusion:Genes associated with the NLR signaling pathway are upregulated in the skin lesions of CLE patients compared to normal controls, supporting the role of the innate immune system in CLE. Further validation studies using experimental methods are needed.References:[1]Enhanced inflammasome activity in systemic lupus erythematosus is mediated via type I interferon upregulation of interferon regulatory factor 1. Liu J, et al. Arth Rheum. 2017; 69(9): 1840-1849.Disclosure of Interests:None declared
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Kim, Gayoung, Kyeong-Hun Choi, Hangeun Kim, and Dae-Kyun Chung. "Alleviation of LPS-Induced Inflammation and Septic Shock by Lactiplantibacillus plantarum K8 Lysates." International Journal of Molecular Sciences 22, no. 11 (May 31, 2021): 5921. http://dx.doi.org/10.3390/ijms22115921.
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We previously showed that Lactiplantibacillus plantarum K8 and its cell wall components have immunoregulatory effects. In this study, we demonstrate that pre-treatment of L. plantarum K8 lysates reduced LPS-induced TNF-α production in THP-1 cells by down-regulating the early signals of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). The down-regulation of signals may be caused by the induction of negative regulators involved in toll-like receptor (TLR)-mediated signaling. However, co-treatment with high concentrations of L. plantarum K8 lysates and lipopolysaccharide (LPS) activated the late signaling of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and NF-κB pathways and resulted in the induction of absent in melanoma 2 (AIM2) inflammasome-mediated interleukin (IL)-1β secretion. Intraperitoneal injection of L. plantarum K8 lysates in LPS-induced endotoxin shock mice alleviated mortality and reduced serum tumor-necrosis factor (TNF)-α, IL-1β, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. In addition, the mRNA levels of TNF-α, IL-1β, and IL-6 decreased in livers from mice injected with L. plantarum K8 followed by LPS. Hematoxylin and eosin (H&E) staining of the liver showed that the cell size was enlarged by LPS injection and slightly reduced by L. plantarum K8 lysate pre-injection followed by LPS injection. Macrophage infiltration of the liver also decreased in response to the combination injection compared with mice injected with only LPS. Taken together, our results show that although L. plantarum K8 lysates differentially regulated the production of LPS-induced inflammatory cytokines in THP-1 cells, the lysates inhibited overall inflammation in mice. Thus, this study suggests that L. plantarum K8 lysates could be developed as a substance that modulates immune homeostasis by regulating inflammation.
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Suresh, Manasa, Bin Li, Xu Huang, Kyle E. Korolowicz, Marta G. Murreddu, Severin O. Gudima, and Stephan Menne. "Agonistic Activation of Cytosolic DNA Sensing Receptors in Woodchuck Hepatocyte Cultures and Liver for Inducing Antiviral Effects." Frontiers in Immunology 12 (October 4, 2021). http://dx.doi.org/10.3389/fimmu.2021.745802.
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Immune modulation for the treatment of chronic hepatitis B (CHB) has gained more traction in recent years, with an increasing number of compounds designed for targeting different host pattern recognition receptors (PRRs). These agonistic molecules activate the receptor signaling pathway and trigger an innate immune response that will eventually shape the adaptive immunity for control of chronic infection with hepatitis B virus (HBV). While definitive recognition of HBV nucleic acids by PRRs during viral infection still needs to be elucidated, several viral RNA sensing receptors, including toll-like receptors 7/8/9 and retinoic acid inducible gene-I-like receptors, are explored preclinically and clinically as possible anti-HBV targets. The antiviral potential of viral DNA sensing receptors is less investigated. In the present study, treatment of primary woodchuck hepatocytes generated from animals with CHB with HSV-60 or poly(dA:dT) agonists resulted in increased expression of interferon-gamma inducible protein 16 (IFI16) or Z-DNA-binding protein 1 (ZBP1/DAI) and absent in melanoma 2 (AIM2) receptors and their respective adaptor molecules and effector cytokines. Cytosolic DNA sensing receptor pathway activation correlated with a decline in woodchuck hepatitis virus (WHV) replication and secretion in these cells. Combination treatment with HSV-60 and poly(dA:dT) achieved a superior antiviral effect over monotreatment with either agonist that was associated with an increased expression of effector cytokines. The antiviral effect, however, could not be enhanced further by providing additional type-I interferons (IFNs) exogenously, indicating a saturated level of effector cytokines produced by these receptors following agonism. In WHV-uninfected woodchucks, a single poly(dA:dT) dose administered via liver-targeted delivery was well-tolerated and induced the intrahepatic expression of ZBP1/DAI and AIM2 receptors and their effector cytokines, IFN-β and interleukins 1β and 18. Receptor agonism also resulted in increased IFN-γ secretion of peripheral blood cells. Altogether, the effect on WHV replication and secretion following in vitro activation of IFI16, ZBP1/DAI, and AIM2 receptor pathways suggested an antiviral benefit of targeting more than one cytosolic DNA receptor. In addition, the in vivo activation of ZBP1/DAI and AIM2 receptor pathways in liver indicated the feasibility of the agonist delivery approach for future evaluation of therapeutic efficacy against HBV in woodchucks with CHB.
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Fan, Xiaojiao, Lianying Jiao, and Tengchuan Jin. "Activation and Immune Regulation Mechanisms of PYHIN Family During Microbial Infection." Frontiers in Microbiology 12 (January 25, 2022). http://dx.doi.org/10.3389/fmicb.2021.809412.
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The innate immune system defenses against pathogen infections via patten-recognition receptors (PRRs). PRRs initiate immune responses by recognizing pathogen-associated molecular patterns (PAMPs), including peptidoglycan, lipopolysaccharide, and nucleic acids. Several nucleic acid sensors or families have been identified, such as RIG-I-like receptors (RLRs), Toll-like receptors (TLRs), cyclic GMP-AMP synthase (cGAS), and PYHIN family receptors. In recent years, the PYHIN family cytosolic DNA receptors have increased attention because of their important roles in initiating innate immune responses. The family members in humans include Absent in melanoma 2 (AIM2), IFN-γ inducible protein 16 (IFI16), interferon-inducible protein X (IFIX), and myeloid cell nuclear differentiation antigen (MNDA). The PYHIN family members are also identified in mice, including AIM2, p202, p203, p204, and p205. Herein, we summarize recent advances in understanding the activation and immune regulation mechanisms of the PYHIN family during microbial infection. Furthermore, structural characterizations of AIM2, IFI16, p202, and p204 provide more accurate insights into the signaling mechanisms of PYHIN family receptors. Overall, the molecular details will facilitate the development of reagents to defense against viral infections.
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Zhang, Wen-Juan, Shu-Juan Chen, Shun-Chang Zhou, Su-Zhen Wu, and Hui Wang. "Inflammasomes and Fibrosis." Frontiers in Immunology 12 (June 11, 2021). http://dx.doi.org/10.3389/fimmu.2021.643149.
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Fibrosis is the final common pathway of inflammatory diseases in various organs. The inflammasomes play an important role in the progression of fibrosis as innate immune receptors. There are four main members of the inflammasomes, such as NOD-like receptor protein 1 (NLRP1), NOD-like receptor protein 3 (NLRP3), NOD-like receptor C4 (NLRC4), and absent in melanoma 2 (AIM2), among which NLRP3 inflammasome is the most studied. NLRP3 inflammasome is typically composed of NLRP3, ASC and pro-caspase-1. The activation of inflammasome involves both “classical” and “non-classical” pathways and the former pathway is better understood. The “classical” activation pathway of inflammasome is that the backbone protein is activated by endogenous/exogenous stimulation, leading to inflammasome assembly. After the formation of “classic” inflammasome, pro-caspase-1 could self-activate. Caspase-1 cleaves cytokine precursors into mature cytokines, which are secreted extracellularly. At present, the “non-classical” activation pathway of inflammasome has not formed a unified model for activation process. This article reviews the role of NLRP1, NLRP3, NLRC4, AIM2 inflammasome, Caspase-1, IL-1β, IL-18 and IL-33 in the fibrogenesis.
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Nakaya, Yuki, Jingtao Lilue, Spyridon Stavrou, Eileen A. Moran, and Susan R. Ross. "AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA." mBio 8, no. 4 (July 5, 2017). http://dx.doi.org/10.1128/mbio.00944-17.
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ABSTRACTCytosolic DNAs derived from retrotransposons serve as pathogen-associated molecular patterns for pattern recognition receptors (PRRs) that stimulate the induction of interferons (IFNs) and other cytokines, leading to autoimmune disease. Cyclic GMP-AMP synthase is one PRR that senses retrotransposon DNA, activating type I IFN responses through the stimulator of IFN genes (STING). Absent in melanoma 2 (AIM2)-like receptors (ALRs) have also been implicated in these pathways. Here we show that the mouse ALR IFI205 senses cytosolic retrotransposon DNA independently of cyclic GMP-AMP production. AIM2 antagonizes IFI205-mediated IFN induction activity by sequestering it from STING. We also found that the complement of genes located in the ALR locus in C57BL/6 and AIM2 knockout mice are different and unique, which has implications for interpretation of the sensing of pathogens in different mouse strains. Our data suggest that members of the ALR family are critical to the host IFN response to endogenous DNA.IMPORTANCEAutoimmune diseases like Aicardi-Goutières syndrome and lupus erythematosus arise when cells of the immune system become activated and attack host cells and tissues. We found that DNA generated by endogenous retroviruses and retroelements in inbred mice and mouse cells is recognized by several host proteins found in macrophages that are members of the ALR family and that these proteins both suppress and activate the pathways leading to the generation of cytokines and IFNs. We also show that there is great genetic diversity between different inbred mouse strains in the ALR genes, which might contribute to differential susceptibility to autoimmunity. Understanding how immune cells become activated is important to the control of disease.
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Guo, Mindy Ming-Huey, Ying-Hsien Huang, Feng-Sheng Wang, Ling-Sai Chang, Kuang-Den Chen, and Ho-Chang Kuo. "CD36 is Associated With the Development of Coronary Artery Lesions in Patients With Kawasaki Disease." Frontiers in Immunology 13 (January 27, 2022). http://dx.doi.org/10.3389/fimmu.2022.790095.
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Kawasaki disease (KD) is an autoimmune-like vasculitis of childhood involving the coronary arteries. Macrophages require scavenger receptors such as CD36 to effectively clear cellular debris and induce self-tolerance. In this study, we hypothesized that CD36 plays an important role in the immunopathogenesis of KD, by aiding in the clearance of plasma mitochondrial DNA, and by amplifying the immune response by activating the inflammasome pathway via AIM2. Fifty-two healthy controls, 52 febrile controls, and 102 KD patients were recruited for RT-PCR of target mRNA expression and plasma mitochondrial DNA. Blood samples were obtained 24 hours prior and 21 days after the administration of intravenous immunoglobulin (IVIG) therapy. Patients with acute KD had higher plasma levels of cell-free mitochondrial DNA (ND1, ND4, and COX1), and higher mRNA expressions of CD36 and AIM2 when compared to both healthy and febrile controls. A greater decrease in both CD36 and AIM2 mRNA expression after IVIG therapy was associated with the development of coronary artery lesions. Coronary artery lesions were associated with a larger decrease of CD36 expression following IVIG therapy, which may indicate that prolonged expression of the scavenger receptor may have a protective effect against the development of coronary artery lesions in KD.
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Kumar, Vijay. "The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA." Frontiers in Immunology 11 (February 11, 2021). http://dx.doi.org/10.3389/fimmu.2020.624597.
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The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80–300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.
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Quinones, Quintin J., Qing Ma, Michael P. Smith, Janet Staats, Cliburn Chan, Brian M. Barnes, and Mihai V. Podgoreanu. "Abstract 15894: Adaptations of Innate Immunity in Hibernation: Mechanisms for Protection Against Acute Organ Injury." Circulation 132, suppl_3 (November 10, 2015). http://dx.doi.org/10.1161/circ.132.suppl_3.15894.
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Introduction: Hibernation is a natural molecular adaptation to extreme environmental conditions with important implications for perioperative organ protection. Hypothesis: We hypothesized that the hibernator cardioprotective phenotype is accompanied by altered expression of innate immune pattern-recognition receptors (PRRs) and inflammatory pathways. Methods: LV myocardium, peripheral blood monocytes (PBMC), and plasma were collected from rat, summer AGS, and winter AGS after sham, 3h or 24h ischemia/reperfusion (I/R). Results: Plasma troponin I detection confirmed greater I/R injury in rat compared to AGS (Fig 1). Proteomic profiling of LV myocardium detected multiple differences including higher expression of MyD88 dependent toll-like receptors (TLR) in rat compared to AGS; average levels of TLRs were 1.8 fold higher in rat compared with hibernating AGS. Comparison of PBMCs from rat, summer, and hibernating AGS revealed increased PRR expression and cytokine production in the rat compared to the AGS, along the TLR3/TICAM (Fig2), TLR/MyD88, and AIM2/inflammasome axes. Conclusions: Compared to AGS, rats experience robust inflammasome activation in response to I/R as evidenced by >30-fold increases in AIM2 and Caspase 1. Hibernation state differences in innate immunity exist, including reduced expression of PRRs(TLR1,3, and AIM2); additionally signaling via TLR 3 and 4 is greatly dampened in winter AGS due to nearly absent expression of TICAM1. Circulating immune effector cells in winter AGS have an abrogated response to DAMPs compared to cells from summer AGS or rat, as evidenced by reduced cytokine production.
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Li, Danyang, and Minghua Wu. "Pattern recognition receptors in health and diseases." Signal Transduction and Targeted Therapy 6, no. 1 (August 4, 2021). http://dx.doi.org/10.1038/s41392-021-00687-0.
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AbstractPattern recognition receptors (PRRs) are a class of receptors that can directly recognize the specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells. PRRs bridge nonspecific immunity and specific immunity. Through the recognition and binding of ligands, PRRs can produce nonspecific anti-infection, antitumor, and other immunoprotective effects. Most PRRs in the innate immune system of vertebrates can be classified into the following five types based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs). PRRs are basically composed of ligand recognition domains, intermediate domains, and effector domains. PRRs recognize and bind their respective ligands and recruit adaptor molecules with the same structure through their effector domains, initiating downstream signaling pathways to exert effects. In recent years, the increased researches on the recognition and binding of PRRs and their ligands have greatly promoted the understanding of different PRRs signaling pathways and provided ideas for the treatment of immune-related diseases and even tumors. This review describes in detail the history, the structural characteristics, ligand recognition mechanism, the signaling pathway, the related disease, new drugs in clinical trials and clinical therapy of different types of PRRs, and discusses the significance of the research on pattern recognition mechanism for the treatment of PRR-related diseases.
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Xie, Bingteng, and Aiqin Luo. "Nucleic Acid Sensing Pathways in DNA Repair Targeted Cancer Therapy." Frontiers in Cell and Developmental Biology 10 (April 26, 2022). http://dx.doi.org/10.3389/fcell.2022.903781.
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The repair of DNA damage is a complex process, which helps to maintain genome fidelity, and the ability of cancer cells to repair therapeutically DNA damage induced by clinical treatments will affect the therapeutic efficacy. In the past decade, great success has been achieved by targeting the DNA repair network in tumors. Recent studies suggest that DNA damage impacts cellular innate and adaptive immune responses through nucleic acid-sensing pathways, which play essential roles in the efficacy of DNA repair targeted therapy. In this review, we summarize the current understanding of the molecular mechanism of innate immune response triggered by DNA damage through nucleic acid-sensing pathways, including DNA sensing via the cyclic GMP-AMP synthase (cGAS), Toll-like receptor 9 (TLR9), absent in melanoma 2 (AIM2), DNA-dependent protein kinase (DNA-PK), and Mre11-Rad50-Nbs1 complex (MRN) complex, and RNA sensing via the TLR3/7/8 and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs). Furthermore, we will focus on the recent developments in the impacts of nucleic acid-sensing pathways on the DNA damage response (DDR). Elucidating the DDR-immune response interplay will be critical to harness immunomodulatory effects to improve the efficacy of antitumor immunity therapeutic strategies and build future therapeutic approaches.
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Xie, Bingteng, and Aiqin Luo. "Nucleic Acid Sensing Pathways in DNA Repair Targeted Cancer Therapy." Frontiers in Cell and Developmental Biology 10 (April 26, 2022). http://dx.doi.org/10.3389/fcell.2022.903781.
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The repair of DNA damage is a complex process, which helps to maintain genome fidelity, and the ability of cancer cells to repair therapeutically DNA damage induced by clinical treatments will affect the therapeutic efficacy. In the past decade, great success has been achieved by targeting the DNA repair network in tumors. Recent studies suggest that DNA damage impacts cellular innate and adaptive immune responses through nucleic acid-sensing pathways, which play essential roles in the efficacy of DNA repair targeted therapy. In this review, we summarize the current understanding of the molecular mechanism of innate immune response triggered by DNA damage through nucleic acid-sensing pathways, including DNA sensing via the cyclic GMP-AMP synthase (cGAS), Toll-like receptor 9 (TLR9), absent in melanoma 2 (AIM2), DNA-dependent protein kinase (DNA-PK), and Mre11-Rad50-Nbs1 complex (MRN) complex, and RNA sensing via the TLR3/7/8 and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs). Furthermore, we will focus on the recent developments in the impacts of nucleic acid-sensing pathways on the DNA damage response (DDR). Elucidating the DDR-immune response interplay will be critical to harness immunomodulatory effects to improve the efficacy of antitumor immunity therapeutic strategies and build future therapeutic approaches.