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1
Hargarten, Jessica C., Tyler C. Moore, Thomas M. Petro, Kenneth W. Nickerson, and Audrey L. Atkin. "Candida albicans Quorum Sensing Molecules Stimulate Mouse Macrophage Migration." Infection and Immunity 83, no. 10 (July 20, 2015): 3857–64. http://dx.doi.org/10.1128/iai.00886-15.
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The polymorphic commensal fungusCandida albicanscauses life-threatening disease via bloodstream and intra-abdominal infections in immunocompromised and transplant patients. Although host immune evasion is a common strategy used by successful human fungal pathogens,C. albicansprovokes recognition by host immune cells less capable of destroying it. To accomplish this,C. albicanswhite cells secrete a low-molecular-weight chemoattractive stimulant(s) of macrophages, a phagocyte that they are able to survive within and eventually escape from.C. albicansopaque cells do not secrete this chemoattractive stimulant(s). We report here a physiological mechanism that contributes to the differences in the interaction ofC. albicanswhite and opaque cells with macrophages.E,E-Farnesol, which is secreted by white cells only, is a potent stimulator of macrophage chemokinesis, whose activity is enhanced by yeast cell wall components and aromatic alcohols.E,E-farnesol results in up to an 8.5-fold increase in macrophage migrationin vitroand promotes a 3-fold increase in the peritoneal infiltration of macrophagesin vivo. Therefore, modulation of farnesol secretion to stimulate host immune recognition by macrophages may help explain why this commensal is such a successful pathogen.
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Shaw, Maureen A., Zhen Gao, and Eric S. Mullins. "Plasmin(ogen) Mediates Macrophage Migration in a Fibrin(ogen) Dependent Mechanism." Blood 128, no. 22 (December 2, 2016): 18. http://dx.doi.org/10.1182/blood.v128.22.18.18.
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Abstract Mounting evidence ties both fibrin(ogen) and plasmin(ogen) to inflammatory diseases. Indeed, both fibrin(ogen) and plasmin(ogen) have been linked to critical macrophage functions in multiple disease processes. Migration of macrophages to sites of sterile inflammation is, at least partially, dependent on plasmin(ogen). Mice lacking plasminogen, when challenged with sterile thioglycollate-induced peritonitis, have both diminished overall leukocyte migration and decreased macrophage migration. Additionally, macrophage migration defects have been identified in both mice lacking plasminogen and plasminogen receptors. Plasmin has many targets that may play a role in supporting macrophage migration. In addition to proteolysis of fibrin(ogen), plasmin activates matrix metalloprotease (MMP) 2 and MMP9 and cleaves collagen and laminin. Indeed, mice that lack MMP9 have a migration defect similar to mice that lack plasminogen, suggesting that MMP9 is a biologically relevant proteolytic target in this context. To further examine the targets of plasmin that regulate macrophage migration, we challenged animals that have individual and combined genetic deficiencies in fibrinogen and plasminogen with thioglycollate-induced peritonitis. We have found that mice that lack fibrinogen alone have a significantly increased migration of macrophages to the peritoneal cavity. Mice with lack of plasminogen alone demonstrated the expected diminution in macrophage migration to the peritoneal cavity. However, mice that were deficient in both plasminogen and fibrinogen demonstrated macrophage migration that was indistinguishable from wildtype. These data suggest that fibrin(ogen) impedes macrophage migration to the peritoneal cavity. To further confirm this mechanism, we examined macrophage migration in a transwell assay in vitro, in response to macrophage chemoattractant protein-1 (MCP-1). Here, a macrophage cell line (RAW 264.7) migration was examined in the absence and presence of fibrin matrices. Macrophages, in the absence of plasminogen, did demonstrate a modest, but statistically significant, increase in migration across the transwell membrane in the absence of fibrinogen. When a fibrin matrix was generated on the transwell membrane, macrophages were essentially unable to cross in the absence of plasminogen. These data further support the concept that macrophages require plasmin(ogen) to cross fibrin matrices. To further explore the plasmin(ogen)-fibrin(ogen) interaction in macrophage migration, we assessed the migration of macrophages to fibrin degradation products (FDPs). First, we examined macrophage transwell migration in response to MCP-1 in the presence of FDPs to assess if FDPs impede macrophage migration. Instead of impeding macrophage migration, FDPs significantly increased macrophage migration across the transwell membrane. Indeed FDPs initiated macrophage migration even in the absence of MCP-1. To confirm that this was FDP induced migration, and not direct plasmin signaling on macrophages, we examined macrophage migration to FDPs in the presence of an irreversible plasmin inhibitor. We again found that plasmin degradation of fibrin was needed for migration, however, further plasmin activity was not required. Taken together, these data suggest that macrophages require plasmin(ogen) to navigate fibrin matrices and that the by-product of this degradation (FDPs) is a signal for additional macrophage migration to sites of fibrin deposition. Disclosures Mullins: Baxalta (now part of Shire): Honoraria; US WorldMeds: Membership on an entity's Board of Directors or advisory committees.
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Mullins, Eric S., Maureen A. Shaw, Zhen Gao, and Matthew J. Flick. "Plasmin-Mediated Fibrinolysis Enables Macrophage Migration Via Liberation from Fibrin-αMβ2 Interactions." Blood 132, Supplement 1 (November 29, 2018): 136. http://dx.doi.org/10.1182/blood-2018-99-117018.
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Abstract Mounting evidence ties both fibrin(ogen) and plasmin(ogen) to inflammatory diseases. Indeed, both fibrin(ogen) and plasmin(ogen) have been linked to critical macrophage functions in multiple disease processes. Migration of macrophages to sites of sterile inflammation is, at least partially, dependent on plasmin(ogen). Mice lacking plasminogen, when challenged with sterile thioglycollate-induced peritonitis, have both diminished overall leukocyte migration and decreased macrophage migration. Additionally, macrophage migration defects have been identified in both mice lacking plasminogen and plasminogen receptors. Plasmin has many targets that may play a role in supporting macrophage migration. In addition to proteolysis of fibrin(ogen), plasmin activates matrix metalloprotease (MMP) 2 and MMP9 and cleaves collagen and laminin. Indeed, mice that lack MMP9 have a migration defect similar to mice that lack plasminogen, suggesting that MMP9 is a biologically relevant proteolytic target in this context. To further examine the targets of plasmin that regulate macrophage migration, we challenged animals that have individual and combined genetic deficiencies in fibrinogen and plasminogen with thioglycollate-induced peritonitis. We have found that mice that lack fibrinogen alone have a significantly increased migration of macrophages to the peritoneal cavity. Mice that lack plasminogen alone demonstrated the expected diminution in macrophage migration to the peritoneal cavity. However, mice that were deficient in both plasminogen and fibrinogen demonstrated macrophage migration that was indistinguishable from wildtype. These data suggest that fibrin(ogen) impedes macrophage migration to the peritoneal cavity. To further confirm this mechanism, we examined macrophage migration in a transwell assay in vitro. Here, a macrophage cell line (RAW 264.7 or BMDM) migration was examined in the absence and presence of fibrin matrices. Macrophages, in the presence of plasminogen, did demonstrate a modest, but statistically significant, increase in migration across the transwell membrane in the absence of fibrinogen. When a fibrin matrix was generated on the transwell membrane, macrophages were essentially unable to cross in the absence of plasminogen. These data further support the concept that macrophages require plasmin(ogen) to cross fibrin matrices. We further sought to determine if the fibrin-αMβ2 interaction was implicated in the macrophage migration phenotype. To do this, we first examined macrophage migration in vivo in mice expressing a form of fibrinogen that cannot interact with αMβ2, Fibγ390-396A mice. Similar to mice lacking fibrinogen, an increase in peritoneal macrophages was observed at 72 hours following a challenge with 4% thioglycollate. To confirm that this was related to the fibrin-αMβ2 interaction, and not due to abnormal factor XIII crosslinking, factor XIII deficient animals were also challenged with thioglycollate induced peritonitis. Mice lacking factor XIII exhibited no difference from wildtype in this model of peritonitis. We further confirmed in the in vitro transwell migration assay that macrophages were able to cross a fibrin barrier, derived from Fibγ390-396A mice, in the absence of plasminogen. Taken together, these data suggest that plasmin allows macrophage migration via liberation from the fibrin-αMβ2 interaction. Disclosures Mullins: Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Munugalavadla, Veerendra, Jovencio Borneo, David A. Ingram, and Reuben Kapur. "p85α subunit of class IA PI-3 kinase is crucial for macrophage growth and migration." Blood 106, no. 1 (July 1, 2005): 103–9. http://dx.doi.org/10.1182/blood-2004-10-4041.
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Macrophages play an essential role in defending against invading pathogens by migrating to the sites of infection, removing apoptotic cells, and secreting inflammatory cytokines. The molecular mechanisms whereby macrophages regulate these processes are poorly understood. Using bone marrow–derived macrophages (BMMs) deficient in the expression of p85α-subunit of class IA phosphatidylinositol 3 (PI-3) kinase, we demonstrate 50% reduction in proliferation in response to macrophage–colony-stimulating factor (M-CSF) as well as granulocyte macrophage–colony-stimulating factor (GM-CSF) compared with wild-type controls. Furthermore, p85α–/– BMMs demonstrate a significant reduction in migration in a wound-healing assay compared with wild-type controls. The reduction in migration due to p85α deficiency in BMMs is associated with reduced adhesion and directed migration on fibronectin and vascular cell adhesion molecule-1. In addition, deficiency of p85α in BMMs also results in defective phagocytosis of sheep red blood cells. Biochemically, loss of p85α in BMMs results in reduced activation of Akt and Rac, but not Erk (extracellular signal-related kinase) mitogen-activated protein (MAP) kinase. Taken together, our results provide genetic evidence for the importance of p85α in regulating both actin- and growth-based functions in macrophages, and provide a potential therapeutic target for the treatment of diseases involving macrophages, including inflammation.
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Kobayakawa, Kazu, Yasuyuki Ohkawa, Shingo Yoshizaki, Tetsuya Tamaru, Takeyuki Saito, Ken Kijima, Kazuya Yokota, et al. "Macrophage centripetal migration drives spontaneous healing process after spinal cord injury." Science Advances 5, no. 5 (May 2019): eaav5086. http://dx.doi.org/10.1126/sciadv.aav5086.
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Traumatic spinal cord injury (SCI) brings numerous inflammatory cells, including macrophages, from the circulating blood to lesions, but pathophysiological impact resulting from spatiotemporal dynamics of macrophages is unknown. Here, we show that macrophages centripetally migrate toward the lesion epicenter after infiltrating into the wide range of spinal cord, depending on the gradient of chemoattractant C5a. However, macrophages lacking interferon regulatory factor 8 (IRF8) cannot migrate toward the epicenter and remain widely scattered in the injured cord with profound axonal loss and little remyelination, resulting in a poor functional outcome after SCI. Time-lapse imaging and P2X/YRs blockade revealed that macrophage migration via IRF8 was caused by purinergic receptors involved in the C5a-directed migration. Conversely, pharmacological promotion of IRF8 activation facilitated macrophage centripetal movement, thereby improving the SCI recovery. Our findings reveal the importance of macrophage centripetal migration via IRF8, providing a novel therapeutic target for central nervous system injury.
6
Yakubenko, Valentin P., and Tatiana P. Ugarova. "The Role of Integrin αDβ2 in Macrophage Migration." Blood 106, no. 11 (November 16, 2005): 2215. http://dx.doi.org/10.1182/blood.v106.11.2215.2215.
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Abstract Integrin αDβ2 (CD11d/CD18), the most recently discovered member of the β2 sub-family of adhesion receptors, is strongly upregulated on macrophage foam cells which underscores its potential role in atherosclerosis. However, the contribution of αDβ2 to monocyte/macrophage adhesive reactions and the significance of its overexpression on these cells remain unknown. Recently we characterized αDβ2 as a multiligand receptor capable of binding many extracellular matrix proteins with the recognition specificity overlapping that of the major myeloid-specific integrin αMβ2 (Mac-1). We hypothesized that the αDβ2 ability to bind numerous ligands in the extracellular matrix and its capacity to be upregulated to high density on the surface of macrophages may modulate cell adhesiveness and, thus, affect migration. To evaluate the role of αDβ2 in migration, we generated model and natural cells expressing different densities of αDβ2 and tested their migration to different extracellular matrix proteins. In vitro studies demonstrated that αDβ2 expressed at low densities, either on the surface of HEK293 cells or the mouse macrophage cell line IC-21, supported migration which was partially inhibited by anti-αD function-blocking antibodies. Furthermore, β1 and β3 integrins expressed on HEK293 cells and IC-21 macrophages, respectively, contributed to migration because anti-β1 and anti-β3 antibodies inhibited migration. Increased expression of αDβ2 on the surface of HEK293 cells and its upregulation by PMA on IC-21 macrophages resulted in the inhibition of cell migration. Ligation of αDβ2 with anti-αD antibodies restored β1- and β3-driven cell migration by means of removing restraints imposed by the excess of the αDβ2-ligand adhesive bonds. To test the possibility that progressive upregulation of αDβ2 can block macrophage migration in vivo, we assessed the effect of anti-αD function blocking antibodies using the thioglycollate-induced peritonitis model. More than 4-fold upregulation of αDβ2 was detected on macrophages in 72 h after thioglycollate stimulation and, similar to in vitro studies, the numbers of migration macrophages increased in the presence of anti-αD antibodies. These results demonstrate that the density of αDβ2 can modulate cell migration and suggest that low levels of αDβ2 can contribute to monocyte migration while αDβ2 upregulation on differentiated macrophages might facilitate their retention at the site of inflammation.
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Rumianek, Agata N., and David R. Greaves. "How Have Leukocyte In Vitro Chemotaxis Assays Shaped Our Ideas about Macrophage Migration?" Biology 9, no. 12 (December 2, 2020): 439. http://dx.doi.org/10.3390/biology9120439.
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Macrophage chemotaxis is crucial during both onset and resolution of inflammation and unique among all leukocytes. Macrophages are able to switch between amoeboid and mesenchymal migration to optimise their migration through 3D environments. This subtle migration phenotype has been underappreciated in the literature, with macrophages often being grouped and discussed together with other leukocytes, possibly due to the limitations of current chemotaxis assays. Transwell assays were originally designed in the 1960s but despite their long-known limitations, they are still one of the most popular methods of studying macrophage migration. This review aims to critically evaluate transwell assays, and other popular chemotaxis assays, comparing their advantages and limitations in macrophage migration studies.
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Benyamini, Noam, Samah Waked, Lina Bisharat, Noam Bettman, and Tami Katz. "The Effect of Lenalidomide on Multiple Myeloma Associated Macrophages." Blood 128, no. 22 (December 2, 2016): 3689. http://dx.doi.org/10.1182/blood.v128.22.3689.3689.
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Abstract Introduction: In multiple myeloma (MM), accessory cells, such as monocytes and macrophages, located in the bone marrow (BM) tumor microenvironment play a crucial role in the fate of malignant cells. Under the influence of the surrounding milieu, monocytes can change their migratory capacity and differentiate into tumor-associated macrophages (TAMs). In the tumor site, TAMs can alter their profile from M1 macrophages with antitumor activities to M2-like macrophages that support tumor growth. Lenalidomide (Len), an immunomodulatory drug, used for MM treatment, is known to target different immune components inducing inflammatory responses; however, its direct influence on monocyte migration, macrophage differentiation and function in the tumor microenvironment is still unclear. The current study has aimed to explore the effect of Len on monocyte recruitment, macrophage polarization and pro-tumor functions. Methods: Monocytes were isolated from peripheral blood mononuclear cells of healthy donors, using anti-CD14 microbeads. To assess their migration capacity, monocytes were allowed to migrate through transwell insert towards the conditioned medium (CM) obtained from the BM of newly diagnosed MM patients or from MM cell lines (RPMI or U266) in the presence or absence of Len (10µM); the percentage of migrating monocytes was determined by FACS. For macrophage generation, monocytes were cultured with M-CSF followed by incubation with IL-4 to obtain M2 macrophages. To generate TAMs, CM obtained from the BM of MM patients was used. Len was added to the culture every 24 hours. The phenotype and functional properties of the generated macrophages were assessed. Endocytosis was evaluated by an antigen uptake assay. Macrophages were incubated with FITC-dextran at 37°C or 4°C, as a control, for 60 minutes, and analyzed by FACS. To test T cell proliferation, autologous lymphocytes labeled with CFSE, were stimulated with PHA and co-cultured with macrophages. T cell (CD3+) division was assessed by FACS. For IFN-γ secretion evaluation, lymphocytes co-cultured with macrophages were stimulated with PMA and ionomycin. The percentage of T cells expressing IFN-γ was quantified by FACS. Results: Monocyte migration towards CM obtained from MM cell lines (RPMI or U266) or from BM of MM patients (80.89%; n=4; p<0.01, 57.17%; n=4; p<0.01 and 42.9%; n=9; p<0.05, respectively) was significantly higher compared to migration towards normal BM CM (25.39%; n=2). Monocytes treated with Len demonstrated significantly decreased migration toward CM of MM cell lines (RPMI or U266) compared to untreated monocytes (45% vs. 80.8%; n=4 and 30.2% vs. 57.1%; n=4, respectively; p<0.01). The effect of Len on monocyte migration toward patient- derived CM was diverse. While 4 samples demonstrated decreased migration compared to untreated cells [51.1% vs. 59.6%; n=4; p<0.01], in 5 samples it increased [39.8% vs. 29.7%; n=5; n=5; p<0.01]. To evaluate the effect of Len on macrophage polarization we examined their phenotype and functions. Both M2 macrophages and TAMs treated with Len expressed higher levels of M2 markers CD206, CD163, and cytokine IL-10 compared to untreated macrophages. Functional assays showed that Len increased endocytosis of both M2 macrophages [50% vs. 20%; n=5; P<0.01] and TAMs [47.4% vs. 41.4%; n=6; NS]. Exposure to Len led to suppression of T cell proliferation, when T cells were co-cultured with either autologous M2 macrophages [31% vs. 16%; n=4; p<0.05] or TAMs [39.7% vs. 31.5%; n=3; p<0.01]. In addition, M2 macrophages treated with Len demonstrated a reduction in IFN-γ secretion from T cells compared to untreated M2 macrophages (10.6% vs. 7.1%; n=4; NS). Conclusions: This study has demonstrated that Len has a direct effect on monocyte/macrophage behavior in the microenvironment generated by MM cells. Len is found to reduce monocyte migration, support polarization of macrophages towards the M2 phenotype and promote macrophage immunosuppressive functions, such as endocytosis, reduction of T-cell proliferation and inhibition of IFN-γ production. These findings need to be further investigated in in vivo experiments and could support the benefit of using agents targeting specific pathways associated with TAM development in the treatment of MM patients. Disclosures No relevant conflicts of interest to declare.
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Cho, Sun Wook, Young A. Kim, Hyun Jin Sun, Ye An Kim, Byung-Chul Oh, Ka Hee Yi, Do Joon Park, and Young Joo Park. "CXCL16 signaling mediated macrophage effects on tumor invasion of papillary thyroid carcinoma." Endocrine-Related Cancer 23, no. 2 (November 11, 2015): 113–24. http://dx.doi.org/10.1530/erc-15-0196.
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Macrophages in tumor microenvironment have pivotal roles in tumor growth, metastasis, and angiogenesis. We investigated the interacting mechanism of macrophage actions in human papillary thyroid cancer (PTC). Co-cultures of macrophage/PTC significantly increased the cancer cell migration potentials, compared with the PTC culture alone. Treatment of conditioned medium (CM) of macrophage/PTC co-cultures enhanced cell invasions in 3D invasion assay. Cytokine array analysis demonstrated that CM of macrophage/PTC co-cultures contained a high level of CXCL16, while it was not found in CM of PTC culture alone. Treatment with CXCL16 enhanced the cell migration potentials in PTC cells, and blocking CXCL16 signaling using anti-CXCL16 antibody or metalloproteinase inhibitor (TAPI2) attenuated macrophage-mediated enhancement of PTC cell migration potentials. In PTC cells, CXCL16 treatment or co-cultures with macrophages increased Akt phosphorylation, and these macrophage-dependent increases of Akt phosphorylation was inhibited by anti-CXCL16 antibody. Moreover, Akt inhibitor attenuated macrophage-mediated increases of PTC cell migration potential. In macrophages, treatment of macrophage/PTC co-cultured CMs up-regulated CD163, Il10, and CD206, which were attenuated by anti-CXCL16 antibody treatment. Finally, CXCR6 and CXCL16 expressions were evaluated by immunohistochemical staining with a thyroid tissue microarray including 136 PTC. CXCR6 expressions showed positive correlation with the density of CD163+ macrophages and associated with lymph node metastasis. In conclusion, CXCL16 signaling partly mediated macrophage actions on PTC tumor cell invasion and also changed the macrophage phenotypes into M2-macrophages in PTC tumor microenvironment. These data suggested that CXCL16 signaling, a bidirectional player in macrophage-associated tumor microenvironment, might be a potential therapeutic target of human PTC.
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Li, Xue, Deana Mikhalkova, Erhe Gao, Jin Zhang, Valerie Myers, Carmen Zincarelli, Yonghong Lei, et al. "Myocardial injury after ischemia-reperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density." American Journal of Physiology-Heart and Circulatory Physiology 301, no. 5 (November 2011): H1932—H1940. http://dx.doi.org/10.1152/ajpheart.00755.2010.
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Akt2 protein kinase has been shown to promote cell migration and actin polymerization in several cell types, including macrophages. Because migrating macrophages constitute an important inflammatory response after myocardial ischemia, we determined cardiac macrophage expression after ischemia-reperfusion (I/R) injury and cryo-injury in mice lacking Akt2 (Akt2-KO). At 7 days post-I/R, Akt2-KO cardiac tissues showed an increase in immunohistochemical staining for macrophage markers (Galectin 3 and F4/80) compared with wild-type (WT) mice, indicating macrophage density was increased in the injured Akt2-KO myocardium. This change was time dependent because macrophage density was similar between WT and Akt2-KO myocardium at 3 days post-I/R, but by 7 and 14 days post-I/R, macrophage density was significantly increased in Akt2-KO myocardium. Concomitantly, infarct size was larger and cardiac function was reduced in Akt2-KO mice subjected to I/R. However, when cryo-infarction produced similar infarct sizes in the anterior wall in both WT and Akt2-KO mice, macrophage density remained higher in Akt2-KO mouse myocardium, suggesting Akt2 regulates myocardial macrophage density independent of infarct size. Consistently, bone marrow from Akt2-KO mice enhanced myocardial macrophage density in both C57/B6 WT and Akt2-KO recipient mice. Finally, reciprocal ex-vivo coculturing of macrophages and cardiac myocytes showed that activated Akt2-KO peritoneal macrophages had reduced mobility and adhesion when compared with WT littermate controls. Thus, although Akt-2 KO mice did not affect the initial inflammation response after injury and Akt2 deficiency has been shown to impair cell migration or motility in macrophages, our data suggested a novel mechanism in which increasing retention of Akt2-KO macrophages resulted in increasing cardiac Akt2-KO macrophage density in the myocardial space.
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Pixley, Fiona J. "Macrophage Migration and Its Regulation by CSF-1." International Journal of Cell Biology 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/501962.
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Macrophages are terminally differentiated cells of the mononuclear phagocytic lineage and develop under the stimulus of their primary growth and differentiation factor, CSF-1. Although they differentiate into heterogeneous populations, depending upon their tissue of residence, motility is an important aspect of their function. To facilitate their migration through tissues, macrophages express a unique range of adhesion and cytoskeletal proteins. Notably, macrophages do not form large, stable adhesions or actin stress fibers but rely on small, short lived point contacts, focal complexes and podosomes for traction. Thus, macrophages are built to respond rapidly to migratory stimuli. As well as triggering growth and differentiation, CSF-1 is also a chemokine that regulates macrophage migration via activation the CSF-1 receptor tyrosine kinase. CSF-1R autophosphorylation of several intracellular tyrosine residues leads to association and activation of many downstream signaling molecules. However, phosphorylation of just one residue, Y721, mediates association of PI3K with the receptor to activate the major motility signaling pathways in macrophages. Dissection of these pathways will identify drug targets for the inhibition of diseases in which macrophages contribute to adverse outcomes.
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Chung, Hyo-Yeoung, Jung-Hyun Kim, Ik-Hwan Han, and Jae-Sook Ryu. "Polarization of M2 Macrophages by Interaction between Prostate Cancer Cells Treated with Trichomonas vaginalis and Adipocytes." Korean Journal of Parasitology 58, no. 3 (June 26, 2020): 217–27. http://dx.doi.org/10.3347/kjp.2020.58.3.217.
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Trichomonas vaginalis causes inflammation of the prostate and has been detected in tissues of prostate cancers (PCa), prostatitis and benign prostatic hyperplasia. Obesity is a risk factor for PCa and causes a chronic subclinical inflammation. This chronic inflammation further exacerbates adipose tissue inflammation as results of migration and activation of macrophages. Macrophages are the most abundant immune cells in the PCa microenvironment. M2 macrophages, known as Tumor-Associated Macrophages, are involved in increasing cancer malignancy. In this study, conditioned medium (TCM) of PCa cells infected with live trichomonads contained chemokines that stimulated migration of the mouse preadipocytes (3T3-L1 cells). Conditioned medium of adipocytes incubated with TCM (ATCM) contained Th2 cytokines (IL-4, IL-13). Macrophage migration was stimulated by ATCM. In macrophages treated with ATCM, expression of M2 markers increased, while M1 markers decreased. Therefore, it is suggested that ATCM induces polarization of M0 to M2 macrophages. In addition, conditioned medium from the macrophages incubated with ATCM stimulates the proliferation and invasiveness of PCa. Our findings suggest that interaction between inflamed PCa treated with T. vaginalis and adipocytes causes M2 macrophage polarization, so contributing to the progression of PCa.
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Silva, Lakmali Munasinghage, Andrew Gary Lum, Collin Tran, Molly W. Shaw, Zhen Gao, Matthew J. Flick, Niki M. Moutsopoulos, Thomas H. Bugge, and Eric S. Mullins. "Plasmin-mediated fibrinolysis enables macrophage migration in a murine model of inflammation." Blood 134, no. 3 (July 18, 2019): 291–303. http://dx.doi.org/10.1182/blood.2018874859.
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Abstract Efficient migration of macrophages to sites of inflammation requires cell surface–bound plasmin(ogen). Here, we investigated the mechanisms underlying the deficits of plasmin(ogen)-mediated macrophage migration in 2 models: murine thioglycollate-induced peritonitis and in vitro macrophage migration. As previously reported, macrophage migration into the peritoneal cavity of mice in response to thioglycollate was significantly impaired in the absence of plasminogen. Fibrin(ogen) deposition was noted in the peritoneal cavity in response to thioglycollate, with a significant increase in fibrin(ogen) in the plasminogen-deficient mice. Interestingly, macrophage migration was restored in plasminogen-deficient mice by simultaneous imposition of fibrinogen deficiency. Consistent with this in vivo finding, chemotactic migration of cultured macrophages through a fibrin matrix did not occur in the absence of plasminogen. The macrophage requirement for plasmin-mediated fibrinolysis, both in vivo and in vitro, was negated by deletion of the major myeloid integrin αMβ2-binding motif on the γ chain of fibrin(ogen). The study identifies a critical role of fibrinolysis in macrophage migration, presumably through the alleviation of migratory constraints imposed by the interaction of leukocytes with fibrin(ogen) through the integrin αMβ2 receptor.
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Kushchayeva, Yevgeniya, Darya Mishchuk, and Tatiana Ugarova. "The Role of Beta 2 Integrins in Macrophage Migration During Resolution of Inflammation." Blood 114, no. 22 (November 20, 2009): 3600. http://dx.doi.org/10.1182/blood.v114.22.3600.3600.
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Abstract Abstract 3600 Poster Board III-537 The mobilization of blood monocytes and their differentiation into macrophages during the immune-inflammatory response helps to prepare the tissue for resolution. During the resolution phase of inflammation macrophages do not die locally: some cells emigrate by draining lymphatics whereas some remain at the site of inflammation. The major myelo-monocytic integrin αMβ2 (Mac-1, CD11b/CD18), together with two related integrins αDβ2 (CD11d/CD18) and αXβ2 (CD11c/CD18), mediate critical adhesive reactions of monocyte/macrophages. However, the roles of these adhesion receptors in control of macrophage retention at sites of inflammation and their emigration to lymph nodes are unclear. Using a mouse model of sterile peritonitis induced by thioglycollate injection, we examined the dynamics of macrophage β2 integrins during the resolution phase of inflammation. Macrophages were defined by FACS analyses as a population of cells expressing αMβ2high, αDβ2+ and CD115+. The initial population of resident β2, positive for βDβ2 and negative for αXβ2. The thioglycollate-challenged mice showed a ∼4-fold increase in macrophages on day 3 followed by a progressive decrease to normal resident cell numbers by day 13. Expression of αMβ2 on macrophages on day 3 decreased by 2.5-fold as a result of dilution of the initial population of αMβ2high resident macrophages by infiltrating blood monocytes expressing αMβ2low. However, after day 3, the density of αMβ2 on macrophages gradually increased and by day 13 returned to the high levels characteristic of resident macrophages. By contrast, expression of αDβ2 and αXβ2 on inflammatory macrophages increased by 2-fold by day 6-9 compared to that on resident macrophages and then returned to the resident levels by day 3. Thus, although the number of macrophages decreased from day 3 to day 9 by several fold, the population of macrophages which remained in the peritoneum was enriched in cells expressing the high levels of αMβ2 and αDα2. Tracking migration of fluorescently labeled peritoneal cells demonstrated that a population of macrophages which leaves the inflamed peritoneum and enters lymph nodes consists of cells expressing low levels of αMβ2 and αDβ2. These data suggested that upregulation of β2 integrins, especially αMβ2, may be responsible for the retention of macrophages in the peritoneum. Indeed, the rate of macrophage emigration from the peritoneum in the αMβ2-deficient mice was significantly higher than that in wild-type mice. The results indicate that macrophage emigration from the inflamed site is controlled by the level of integrin αMβ2 and αDβ2 with low expressors being migratory and high expressors remaining in the peritoneum. The data also highlight the importance of integrins αDβ2 and αXβ2 as specific markers of inflammatory macrophages. Disclosures: No relevant conflicts of interest to declare.
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Yang, Jing-Xing, Te-Chih Hsiung, Fu-Chun Weng, Shiau-Li Ding, Chin-Pyng Wu, Marco Conti, Tsung-Hsien Chuang, and S.-L. Catherine Jin. "Synergistic effect of phosphodiesterase 4 inhibitor and serum on migration of endotoxin-stimulated macrophages." Innate Immunity 24, no. 8 (November 2018): 501–12. http://dx.doi.org/10.1177/1753425918809155.
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Macrophage migration is an essential step in host defense against infection and wound healing. Elevation of cAMP by inhibiting phosphodiesterase 4 (PDE4), enzymes that specifically degrade cAMP, is known to suppress various inflammatory responses in activated macrophages, but the role of PDE4 in macrophage migration is poorly understood. Here we show that the migration of Raw 264.7 macrophages stimulated with LPS was markedly and dose-dependently induced by the PDE4 inhibitor rolipram as assessed by scratch wound healing assay. Additionally, this response required the involvement of serum in the culture medium as serum starvation abrogated the effect. Further analysis revealed that rolipram and serum exhibited synergistic effect on the migration, and the influence of serum was independent of PDE4 mRNA expression in LPS-stimulated macrophages. Moreover, the enhanced migration by rolipram was mediated by activating cAMP/exchange proteins directly activated by cAMP (Epac) signaling, presumably via interaction with LPS/TLR4 signaling with the participation of unknown serum components. These results suggest that PDE4 inhibitors, together with serum components, may serve as positive regulators of macrophage recruitment for more efficient pathogen clearance and wound repair.
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Tian, Ying, Sheri E. Kelemen, and Michael V. Autieri. "Inhibition of AIF-1 expression by constitutive siRNA expression reduces macrophage migration, proliferation, and signal transduction initiated by atherogenic stimuli." American Journal of Physiology-Cell Physiology 290, no. 4 (April 2006): C1083—C1091. http://dx.doi.org/10.1152/ajpcell.00381.2005.
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Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic, calcium-binding, inflammation-responsive scaffold protein. Several studies have reported increased AIF-1 expression in activated macrophages and have implicated AIF-1 as a marker of activated macrophages. However, the function of AIF-1 in macrophages and the mechanism whereby it participates in macrophage activation are unknown at this time. Immunohistochemical analysis colocalized AIF-1 expression with CD68-positive macrophages in atherosclerotic human coronary arteries. Subsequent experiments were designed to determine a role for AIF-1 in macrophage activation in response to atherogenic stimuli. Stimulation of human and murine macrophages with oxidized LDL significantly increased AIF-1 expression above basal levels. Stable transfection of AIF-1 small interfering RNA (siRNA) in macrophages reduced AIF-1 protein expression by 79% and reduced macrophage proliferation by 52% ( P < 0.01). Inhibition of proliferation was not due to induction of apoptosis. Sequences that did not knock down AIF-1 expression had no effect on proliferation. AIF-1 siRNA expression reduced macrophage migration by 60% ( P < 0.01). Both proliferation and migration of siRNA-expressing macrophages could be restored by adenoviral expression of AIF-1 ( P < 0.001 and 0.005, respectively), suggesting a tight association between AIF-1 expression and macrophage activation. Phosphorylation of Akt, p44/42 MAPK, and p38 kinase were significantly reduced in siRNA macrophages challenged with oxidized LDL ( P < 0.05). Phosphorylation of p38 kinase was significantly inhibited in siRNA macrophages stimulated with T lymphocyte conditioned medium ( P < 0.05). These data indicate that AIF-1 mediates atherogenesis-initiated signaling and activation of macrophages.
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O'Connell, Paul A., Alexi P. Surette, Robert S. Liwski, Per Svenningsson, and David M. Waisman. "S100A10 regulates plasminogen-dependent macrophage invasion." Blood 116, no. 7 (August 19, 2010): 1136–46. http://dx.doi.org/10.1182/blood-2010-01-264754.
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Abstract The plasminogen activation system plays an integral role in the migration of macrophages in response to an inflammatory stimulus, and the binding of plasminogen to its cell-surface receptor initiates this process. Although previous studies from our laboratory have shown the importance of the plasminogen receptor S100A10 in cancer cell plasmin production, the potential role of this protein in macrophage migration has not been investigated. Using thioglycollate to induce a peritoneal inflammatory response, we demonstrate, for the first time, that compared with wild-type (WT) mice, macrophage migration across the peritoneal membrane into the peritoneal cavity in S100A10-deficient (S100A10−/−) mice was decreased by up to 53% at 24, 48, and 72 hours. Furthermore, the number of S100A10-deficient macrophages that infiltrated Matrigel plugs was reduced by 8-fold compared with their WT counterpart in vivo. Compared with WT macrophages, macrophages from S100A10−/− mice demonstrated a 50% reduction in plasmin-dependent invasion across a Matrigel barrier and a 45% reduction in plasmin generation in vitro. This loss in plasmin-dependent invasion was in part the result of a decreased generation of plasmin and a decreased activation of pro-MMP-9 by S100A10-deficient macrophages. This study establishes a direct involvement of S100A10 in macrophage recruitment in response to inflammatory stimuli.
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Sharma, Umesh, Nour-Eddine Rhaleb, Saraswati Pokharel, Pamela Harding, Saman Rasoul, Hongmei Peng, and Oscar A. Carretero. "Novel anti-inflammatory mechanisms ofN-Acetyl-Ser-Asp-Lys-Pro in hypertension-induced target organ damage." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 3 (March 2008): H1226—H1232. http://dx.doi.org/10.1152/ajpheart.00305.2007.
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High blood pressure (HBP) is an important risk factor for cardiac, renal, and vascular dysfunction. Excess inflammation is the major pathogenic mechanism for HBP-induced target organ damage (TOD). N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a tetrapeptide specifically degraded by angiotensin converting enzyme (ACE), reduces inflammation, fibrosis, and TOD induced by HBP. Our hypothesis is that Ac-SDKP exerts its anti-inflammatory effects by inhibiting: 1) differentiation of bone marrow stem cells (BMSC) to macrophages, 2) activation and migration of macrophages, and 3) release of the proinflammatory cytokine TNF-α by activated macrophages. BMSC were freshly isolated and cultured in macrophage growth medium. Differentiation of murine BMSC to macrophages was analyzed by flow cytometry using F4/80 as a marker of macrophage maturation. Macrophage migration was measured in a modified Boyden chamber. TNF-α release by activated macrophages in culture was measured by ELISA. Myocardial macrophage activation in mice with ANG II-induced hypertension was studied by Western blotting of Mac-2 (galectin-3) protein. Interstitial collagen deposition was measured by picrosirius red staining. We found that Ac-SDKP (10 nM) reduced differentiation of cultured BMSC to mature macrophages by 24.5% [F4/80 positivity: 14.09 ± 1.06 mean fluorescent intensity for vehicle and 10.63 ± 0.35 for Ac-SDKP; P < 0.05]. Ac-SDKP also decreased galectin-3 and macrophage colony-stimulating factor-dependent macrophage migration. In addition, Ac-SDKP decreased secretion of TNF-α by macrophages stimulated with bacterial LPS. In mice with ANG II-induced hypertension, Ac-SDKP reduced expression of galectin-3, a protein produced by infiltrating macrophages in the myocardium, and interstitial collagen deposition. In conclusion, this study demonstrates that part of the anti-inflammatory effect of Ac-SDKP is due to its direct effect on BMSC and macrophage, inhibiting their differentiation, activation, and cytokine release. These effects explain some of the anti-inflammatory and antifibrotic properties of Ac-SDKP in hypertension.
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Fang, Chunmin, Juan Yu, Yuechen Luo, Song Chen, Weiqiang Wang, Chunxiao Zhao, Zhina Sun, et al. "Tsc1 is a Critical Regulator of Macrophage Survival and Function." Cellular Physiology and Biochemistry 36, no. 4 (2015): 1406–18. http://dx.doi.org/10.1159/000430306.
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Background/Aims: Tuberous sclerosis complex 1 (Tsc1) has been shown to regulate M1/M2 polarization of macrophages, but the precise roles of Tsc1 in the function and stability of macrophages are not fully understood. Here we show that Tsc1 is required for regulating the survival, migration and phagocytosis of macrophages. Methods: Mice with Tsc1 homozygous deletion in myeloid cells (LysMCreTsc1flox/flox; Tsc1 KO) were obtained by crossing Tsc1flox/flox mice with mice expressing Cre recombinase under the control of Lysozyme promoter (LysMCre). The apoptosis and growth of macrophages were determined by flow cytometry and Real-time PCR (RT-PCR). The phagocytosis was determined using a Vybrant™ phagocytosis assay kit. The migration of macrophages was determined using transwell migration assay. Results: Peritoneal macrophages of Tsc1 KO mice exhibited increased apoptosis and enlarged cell size. Both M1 and M2 phenotypes in Tsc1-deficient macrophages were elevated in steady-state as well as in inflammatory conditions. Tsc1-deficient macrophages demonstrated impaired migration and reduced expression of chemokine receptors including CCR2 and CCR5. Phagocytosis activity and ROS production were enhanced in Tsc1-deficient macrophages. Furthermore, pharmacological inhibition of the mammalian target of rapamycin complex 1 (mTORC1) partially reversed the aberrance of Tsc1-deficient macrophages. Conclusion: Tsc1 plays a critical role in regulating macrophage survival, function and polarization via inhibition of mTORC1 activity.
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Diaz-Jimenez, David, Maria Grazia Petrillo, Jonathan T. Busada, Marcela A. Hermoso, and John A. Cidlowski. "Glucocorticoids mobilize macrophages by transcriptionally up-regulating the exopeptidase DPP4." Journal of Biological Chemistry 295, no. 10 (January 27, 2020): 3213–27. http://dx.doi.org/10.1074/jbc.ra119.010894.
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Glucocorticoids are potent endogenous anti-inflammatory molecules, and their cognate receptor, glucocorticoid receptor (GR), is expressed in nearly all immune cells. Macrophages are heterogeneous immune cells having a central role in both tissue homeostasis and inflammation and also play a role in the pathogenesis of some inflammatory diseases. Paradoxically, glucocorticoids have only a limited efficacy in controlling the resolution of these macrophage-related diseases. Here, we report that the transcriptomes of monocyte-like THP-1 cells and macrophage-like THP-1 cells (THP1-MΦ) have largely conserved gene expression patterns. In contrast, the differentiation to THP1-MΦ significantly altered the sensitivity of gene transcription to glucocorticoids. Among glucocorticoid-regulated genes, we identified the exopeptidase dipeptidyl peptidase-4 (DPP4) as a critical glucocorticoid-responsive gene in THP1-MΦ. We found that GR directly induces DPP4 gene expression by binding to two glucocorticoid-responsive elements (GREs) within the DPP4 promoter. Additionally, we show that glucocorticoid-induced DPP4 expression is blocked by the GR antagonist RU-486 and by GR siRNA transfection and that DPP4 enzyme activity is reduced by DPP4 inhibitors. Of note, glucocorticoids highly stimulated macrophage mobility; unexpectedly, DPP4 mediated the glucocorticoid-induced macrophage migration, and siRNA-mediated knockdowns of GR and DPP4 blocked dexamethasone-induced THP1-MΦ migration. Moreover, glucocorticoid-induced DPP4 activation was also observed in proinflammatory M1-polarized murine macrophages, as well as peritoneal macrophages, and was associated with increased macrophage migration. Our results indicate that glucocorticoids directly up-regulate DPP4 expression and thereby induce migration in macrophages, potentially explaining why glucocorticoid therapy is less effective in controlling macrophage-dominated inflammatory disorders.
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Wright, J. R., and D. C. Youmans. "Pulmonary surfactant protein A stimulates chemotaxis of alveolar macrophage." American Journal of Physiology-Lung Cellular and Molecular Physiology 264, no. 4 (April 1, 1993): L338—L344. http://dx.doi.org/10.1152/ajplung.1993.264.4.l338.
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Pulmonary surfactant modulates several functions of alveolar macrophages including phagocytosis, killing, and chemotaxis. We hypothesized that the reported stimulatory effect of surfactant on macrophage migration was mediated by one of the surfactant proteins, SP-A. We found that macrophage migration was stimulated by SP-A in a concentration-dependent manner. A concentration of 105 micrograms SP-A/ml enhanced migration approximately 10-fold. Heat treatment or reduction and alkylation of SP-A reduced its stimulatory effect. A checker-board analysis showed that SP-A stimulated migration primarily by enhancing chemotaxis (directed movement) rather than chemokinesis (random movement). The interaction of SP-A with macrophages may be mediated at least partly by the collagen-like domain of SP-A. We speculate that SP-A may play a multifunctional role in regulating pulmonary immune response by stimulating multiple macrophage functions.
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Vilic, I., and L. M. Prokic. "Negative correlation between maorophage proooagulant and migraion ability in the course of inflammation." Mediators of Inflammation 5, no. 4 (1996): 271–75. http://dx.doi.org/10.1155/s0962935196000397.
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The importance of macrophage procoagulant activity (PCA) to cell migration is presumed. In this study we assayed the relationship between the two functions in guinea-pig peritoneal resident macrophages and cells elicited by a sterile inflammation induction, which lasted up to 6 days. The findings pointed to anin vivoinduction of PCA in macrophages, which declined with time during inflammation. A clear negative correlation between PCA and random migration ability was demonstrated. Our results suggest that the local induction of coagulation by macrophages may immobilize the cells at the site of inflammation.
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Tauzin, Sebastien, Taylor W. Starnes, Francisco Barros Becker, Pui-ying Lam, and Anna Huttenlocher. "Redox and Src family kinase signaling control leukocyte wound attraction and neutrophil reverse migration." Journal of Cell Biology 207, no. 5 (December 8, 2014): 589–98. http://dx.doi.org/10.1083/jcb.201408090.
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Tissue damage induces early recruitment of neutrophils through redox-regulated Src family kinase (SFK) signaling in neutrophils. Redox-SFK signaling in epithelium is also necessary for wound resolution and tissue regeneration. How neutrophil-mediated inflammation resolves remains unclear. In this paper, we studied the interactions between macrophages and neutrophils in response to tissue damage in zebrafish and found that macrophages contact neutrophils and induce resolution via neutrophil reverse migration. We found that redox-SFK signaling through p22phox and Yes-related kinase is necessary for macrophage wound attraction and the subsequent reverse migration of neutrophils. Importantly, macrophage-specific reconstitution of p22phox revealed that macrophage redox signaling is necessary for neutrophil reverse migration. Thus, redox-SFK signaling in adjacent tissues is essential for coordinated leukocyte wound attraction and repulsion through pathways that involve contact-mediated guidance.
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Jerebtsova, Marina, Asrar Ahmad, Namita Kumari, Ornela Rutagarama, and Sergei Nekhai. "Oxygen Levels Affect Macrophage HIV-1 Gene Expression and Delay Resolution of Inflammation in HIV-Tg Mice." Viruses 12, no. 3 (March 1, 2020): 277. http://dx.doi.org/10.3390/v12030277.
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While antiretroviral therapy increases the longevity of people living with HIV (PLWH), about 30% of this population suffers from three or more concurrent comorbidities, whose mechanisms are not well understood. Chronic activation and dysfunction of the immune system could be one potential cause of these comorbidities. We recently demonstrated reduced macrophage infiltration and delayed resolution of inflammation in the lungs of HIV-transgenic mice. Additionally, trans-endothelial migration of HIV-positive macrophages was reduced in vitro. Here, we analyze macrophages’ response to LPS challenge in the kidney and peritoneum of HIV-Tg mice. In contrast to the lung infiltration, renal and peritoneal macrophage infiltrations were similar in WT and HIV-Tg mice. Higher levels of HIV-1 gene expression were detected in lung macrophages compared to peritoneal macrophages. In peritoneal macrophages, HIV-1 gene expression was increased when they were cultured at 21% O2 compared to 5% O2, inversely correlating with reduced trans-endothelial migration at higher oxygen levels in vitro. The resolution of macrophage infiltration was reduced in both the lung and the peritoneal cavity of HIV-Tg mice. Taken together, our study described the organ-specific alteration of macrophage dynamics in HIV-Tg mice. The delayed resolution of macrophage infiltration might constitute a risk factor for the development of multiple comorbidities in PLWH.
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Sakamoto, Wataru, and Jun Nishihira. "Macrophage migration inhibitory factor(MIF) of macrophages and vitamine E." Ensho 19, no. 2 (1999): 87–92. http://dx.doi.org/10.2492/jsir1981.19.87.
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Bauerle, Kevin Thomas, Jisu Oh, Amy Elizabeth Riek, Adriana Dusso, Anabel L. Castro-Grattoni, R. Ariel Gomez, Maria L. Sequeira-Lopez, and Carlos Bernal-Mizrachi. "Vitamin D Deficiency Induces Macrophage Pro-Inflammatory Phenotype via ER Stress-Mediated Activation of Renin-Angiotensin System." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A304—A305. http://dx.doi.org/10.1210/jendso/bvab048.620.
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Abstract Chronic inflammation and local activation of the renin-angiotensin-aldosterone system (RAAS) play a pivotal role in the pathogenesis and progression of diabetic complications. In patients with type 2 diabetes (T2DM), the prevalence of vitamin D deficiency is almost twice that of non-diabetics, and vitamin d deficiency nearly doubles the risk of developing hypertension and cardiovascular complications compared to diabetics with normal vitamin D levels. Interestingly, mice lacking the vitamin D receptor (VDR) in macrophages (KODMAC) develop renin-dependent hypertension, insulin resistance, and inflammation via up-regulation of macrophage ER stress. Macrophages also express all major components of the RAAS system. However, little is known about the regulation of macrophage-generated renin and its role in modulating the sequelae of VDR signaling in macrophage function and cytokine production. This study found that KODMAC macrophages and vitamin D-deficient macrophages have increased expression and secretion of renin, angiotensin II, ACE, and AT1 receptor and that adhesion, migration, and cytokine release were also increased. Inhibition of ER stress in KODMAC macrophages and vitamin D-deficient macrophages with 4-Phenylbutyric acid (PBA) reduced RAS gene expression and macrophage pro-inflammatory phenotype. Renin 1c gene deletion decreased macrophage adhesion, migration, and cytokine release compared to macrophages with disrupted VDR signaling. Notably, disruption of VDR signaling induced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) expression in macrophages, and upregulation of renin expression in response to vitamin D deficiency was blunted in PCG1α-deficient macrophages. In conclusion, our findings delineate a mechanism by which impaired VDR signaling induces ER stress to drive PGC1α-dependent expression of renin and RAAS hyperactivation, thereby altering macrophage function and cytokine production. These data implicate RAAS as an essential mediator of VDR-mediated macrophage function and support ongoing investigations of VDR and RAAS modulation as therapeutic approaches in the management of T2DM and its complications.
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Aerbajinai, Wulin, Lunhua Liu, Kyung Chin, and Griffin P. Rodgers. "Glia Maturation Factor-Gamma Regulates Macrophage Migration Through Control Recycling of alpha5beta1 Integrin in Endosome." Blood 120, no. 21 (November 16, 2012): 3273. http://dx.doi.org/10.1182/blood.v120.21.3273.3273.
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Abstract Abstract 3273 Macrophages play an essential role in defending against invading pathogens by migrating to the sites of infection, removing apoptotic cells, and secreting inflammatory cytokines. Macrophage migration is a critical step in the regulation of immune response and is also associated with many chronic inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, atherosclerosis and cancer. Thus, understanding the mechanisms controlling macrophage migration within different environments is of paramount importance. Although it is clear that adhesion signaling via integrin receptors and the surrounding ECM play a significant role in regulating migration of macrophages to site of inflammation, the underlying cellular and molecular mechanisms responsible for these process is still not fully characterized. Defining the molecular circuits through which integrins regulate macrophage motility is therefore important for gaining a better understanding of macrophage function. Glia maturation factor gamma (GMFG), a novel ADF/cofilin superfamily protein that is predominantly expressed in inflammatory cells, has been implicated in regulating actin reorganization. We have previously demonstrated that GMFG plays a role in regulating neutrophil chemotaxis and migration. We now examine whether GMFG has similar effects on macrophage and the cellular mechanism for these effects by using small-interfering RNA technic to knockdown GMFG in human macrophage like THP-1cells. Knockdown of endogenous GMFG results in significantly reduced chemotactic migration toward fMLP and enhanced adhesion on fibronectin compared with control siRNA transfected cells. Flow cytometry analysis shows that GMFG-knockdown cells expresses significant amount of α5β1 integrin on the surface compared with control cells. Confocal microscopy analysis exhibited that GMFG was distributed throughout the cytosol and colocalized with the multiple endocytic compartment such as early endosome marker EEA1, Rab5, Rab4 and Rab11. Importantly, we found that most of the α5β1 integrins accumulated in clusters at the rear of the GMFG-knockdown cells, along with colocalization with endosome marker EEA1, rather than localization toward the leading edge in response to fMLP stimulation in control cells. These results suggest that impaired efficient α5β1 integrin recycling cause to increased adhesion, which is responsible for reduced macrophage migration on fibronectin in GMFG depletion macrophages. Accordingly, GMFG is required for proper trafficking of endosomal α5β1 integrin to the plasma membrane and is fundamental for integrin-mediated macrophage motility. Disclosures: No relevant conflicts of interest to declare.
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Königs, Volker, Richard Jennings, Thomas Vogl, Markus Horsthemke, Anne C. Bachg, Yan Xu, Kay Grobe, et al. "Mouse Macrophages Completely Lacking Rho Subfamily GTPases (RhoA, RhoB, and RhoC) Have Severe Lamellipodial Retraction Defects, but Robust Chemotactic Navigation and Altered Motility." Journal of Biological Chemistry 289, no. 44 (September 11, 2014): 30772–84. http://dx.doi.org/10.1074/jbc.m114.563270.
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RhoA is thought to be essential for coordination of the membrane protrusions and retractions required for immune cell motility and directed migration. Whether the subfamily of Rho (Ras homolog) GTPases (RhoA, RhoB, and RhoC) is actually required for the directed migration of primary cells is difficult to predict. Macrophages isolated from myeloid-restricted RhoA/RhoB (conditional) double knock-out (dKO) mice did not express RhoC and were essentially “pan-Rho”-deficient. Using real-time chemotaxis assays, we found that retraction of the trailing edge was dissociated from the advance of the cell body in dKO cells, which developed extremely elongated tails. Surprisingly, velocity (of the cell body) was increased, whereas chemotactic efficiency was preserved, when compared with WT macrophages. Randomly migrating RhoA/RhoB dKO macrophages exhibited multiple small protrusions and developed large “branches” due to impaired lamellipodial retraction. A mouse model of peritonitis indicated that monocyte/macrophage recruitment was, surprisingly, more rapid in RhoA/RhoB dKO mice than in WT mice. In comparison with dKO cells, the phenotypes of single RhoA- or RhoB-deficient macrophages were mild due to mutual compensation. Furthermore, genetic deletion of RhoB partially reversed the motility defect of macrophages lacking the RhoGAP (Rho GTPase-activating protein) myosin IXb (Myo9b). In conclusion, the Rho subfamily is not required for “front end” functions (motility and chemotaxis), although both RhoA and RhoB are involved in pulling up the “back end” and resorbing lamellipodial membrane protrusions. Macrophages lacking Rho proteins migrate faster in vitro, which, in the case of the peritoneum, translates to more rapid in vivo monocyte/macrophage recruitment.
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Salo, Henna, Heshuang Qu, Dimitra Mitsiou, Hannah Aucott, Jinming Han, Xingmei Zhang, Cecilia Aulin, and Helena Erlandsson Harris. "Disulfide and Fully Reduced HMGB1 Induce Different Macrophage Polarization and Migration Patterns." Biomolecules 11, no. 6 (May 28, 2021): 800. http://dx.doi.org/10.3390/biom11060800.
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Macrophage plasticity enables cells to obtain different functions over a broad proinflammatory and repairing spectrum. In different conditions, macrophages can be induced by high-mobility group box 1 (HMGB1), a nuclear DNA-binding protein that activates innate immunity, to polarize towards a pro- (M1) or anti-inflammatory (M2) phenotype. In this study, we investigated the phenotypes of murine bone-marrow-derived macrophages (BMDMs) induced by different HMGB1 redox isoforms in depth. Our results demonstrate that disulfide HMGB1 (dsHMGB1) induces a unique macrophage phenotype that secretes pro-inflammatory cytokines, rather than inducing metabolic changes leading to nitric oxide production. Fully reduced HMGB1 (frHMGB1) did not induce macrophage polarization. The migrating function of BMDMs was measured by scratch assay after the stimulation with dsHMGB1 and frHMGB1. Both dsHMGB1 and frHMGB1 induced cell migration. We found that dsHMGB1 mediates cytokine secretion and cellular motility, mainly through toll-like receptor 4 (TLR4). Importantly, our data shows that dsHMGB1 and frHMGB1 induce distinct BMDM polarization phenotypes, and that dsHMGB1 induces a unique phenotype differing from the classical proinflammatory macrophage phenotype.
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Lu, Tianjing, Wen-Jye Lin, Kouji Izumi, Xiaohai Wang, Defeng Xu, Lei-Ya Fang, Lei Li, Qi Jiang, Jie Jin, and Chawnshang Chang. "Targeting Androgen Receptor to Suppress Macrophage-induced EMT and Benign Prostatic Hyperplasia (BPH) Development." Molecular Endocrinology 26, no. 10 (October 1, 2012): 1707–15. http://dx.doi.org/10.1210/me.2012-1079.
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Abstract Early studies suggested macrophages might play roles in inflammation-associated benign prostatic hyperplasia (BPH) development, yet the underlying mechanisms remain unclear. Here we first showed that CD68+ macrophages were identified in both epithelium and the stromal area of human BPH tissues. We then established an in vitro co-culture model with prostate epithelial and macrophage cell lines to study the potential impacts of infiltrating macrophages in the BPH development and found that co-culturing prostate epithelial cells with macrophages promoted migration of macrophages. In a three-dimensional culture system, the sphere diameter of BPH-1 prostate cells was significantly increased during coculture with THP-1 macrophage cells. Mechanism dissection suggested that expression levels of epithelial-mesenchymal transition (EMT) markers, such as N-cadherin, Snail, and TGF-β2, were increased, and administration of anti-TGF-β2 neutralizing antibody during co-culture suppressed the EMT and THP-1-mediated growth of BPH-1 cells, suggesting THP-1 might go through EMT to influence the BPH development and progression. Importantly, we found that modulation of androgen receptor (AR) in BPH-1 and mPrE cells significantly increased THP-1 and RAW264.7 cell migration, respectively, and enhanced expression levels of EMT markers, suggesting that AR in prostate epithelial cells might play a role in promoting macrophage-mediated EMT in prostate epithelial cells. Silencing AR function via an AR degradation enhancer, ASC-J9, decreased the macrophage migration to BPH-1 cells and suppressed EMT marker expression. Together, these results provide the first evidence to demonstrate that prostate epithelial AR function is important for macrophage-mediated EMT and proliferation of prostate epithelial cells, which represents a previously unrecognized role of AR in the cross-talk between macrophages and prostate epithelial cells. These results may provide new insights for a new therapeutic approach to battle BPH via targeting AR and AR-mediated inflammatory signaling pathways.
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Podolnikova, Nataly P., Kyubeom Oh, Ivan S. Yermolenko, and Tatiana P. Ugarova. "An Altered Macrophage Migration In Adipose Tissue Of Integrin Mac-1 (CD11b/CD18) Deficient Mice." Blood 122, no. 21 (November 15, 2013): 1031. http://dx.doi.org/10.1182/blood.v122.21.1031.1031.
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Abstract It has recently been recognized that obesity, a critical factor contributing to the number of abnormalities constituting the metabolic syndrome, is associated with adipose tissue inflammation which is attributable in large part to the increased numbers of infiltrating macrophages. Integrins and, in particular, the major myeloid-specific integrin αMβ2 (Mac-1) plays an essential role in leukocyte migration. We have found that during the period of 12-36 weeks, Mac-1-/- mice gained more weight on normal chow diet than control mice, which was due to the increase of white fat mass (∼1.7- and 3.3-fold for males and females, respectively) and not a result of increased food intake. To gain insight into the mechanisms that regulate fat storage in Mac-1-/- mice, we determined the number of macrophages present in omental fat band (OFB) which, similar to other fat depots, underwent the mass increase. Unexpectedly, the number of macrophages per mg of OFB was less in Mac-1-/- mice than that in wild-type mice at all ages examined with the largest difference observed at 6 weeks (∼2.9- and 2.5-fold for males and females, respectively), implicating Mac-1 in the control of macrophage influx and/or retention within OFB. To examine the role of Mac-1 in migration, resident and thioglycollate-elicited inflammatory macrophages were isolated from the peritoneum, labeled with PKH-26 fluorescent dye and their migration to and from OFB were determined by measuring tissue fluorescence. For the “walk-in” experiments, OFB was made “empty” by incubating the tissue for 24 h in a cell culture medium to release OFB-associated macrophages and lymphocytes. “Walk-out” experiments were performed by first filling OFB with labeled macrophages and then tracking their emigration from the tissue. The analyses of the kinetics of macrophage migration showed that both resident and inflammatory Mac-1-/- macrophages arrive to and exit from OFB faster than their wild-type counterparts. For example, the number of Mac-1-/- resident and inflammatory macrophages that accumulated in OFB after 4 h was 11±2.8 and 2.4±0.38 -fold higher than that of wild-type cells. Likewise, the rate of emigration from OFB for both resident and inflammatory was higher for Mac-/- macrophages than that of wild-type cells (4.4±0.55 and 2.8±0.15 after 6 h for inflammatory and resident macrophages, respectively). The distinction in migration was not due to the differences in cell adhesive properties as wild-type and Mac-/- macrophages adhered to the same extent to plastic dishes. To examine macrophage migration in vivo, PKH-26-labeled wild-type and Mac-/- macrophages were injected into the peritoneum of wild-type mice and their migration to and emigration from OFB was tracked by determining the fluorescence intensity of OFB excised after selected time points. Similar to their behavior in vitro, both resident and inflammatory Mac-/- macrophages migrated faster to and emigrated from OFB than wild-type cells. In addition, after the arrival to OFB, wild-type macrophages organized in large clusters, a pattern distinct from Mac-/- cells which were scattered on the surface and within the tissue. These results suggest that the reduced number of macrophages observed in OFB of Mac-/- mice may be due to their enhanced mobility and reduced capacity to establish adhesive bonds within the OFB tissue resulting in the reduced retention and increased turnover. Since less macrophages is present in fat in the overweight Mac-/- mice than in normal wild-type mice, the data also indicate that the increase in body fat can be dissociated from the increase in macrophage numbers in fat. Disclosures: No relevant conflicts of interest to declare.
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Lee, Sharon Wei Ling, R. J. Seager, Felix Litvak, Fabian Spill, Je Lin Sieow, Penny Hweixian Leong, Dillip Kumar, et al. "Integrated in silico and 3D in vitro model of macrophage migration in response to physical and chemical factors in the tumor microenvironment." Integrative Biology 12, no. 4 (April 2020): 90–108. http://dx.doi.org/10.1093/intbio/zyaa007.
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Abstract Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor macrophage functions; however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and macrophages to study how IF affects macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased macrophage migration directedness and speed. Interestingly, there was no additive effect on macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an in silico model that couples chemokine-mediated signaling with mechanosensing networks to explain our in vitro observations. In our model design, we propose IL-8, CCL2, and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, in vitro macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2 or to the co-addition of a sub-saturating concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated in silico and 3D in vitro approach to aid the design of tumor-associated macrophage-based immunotherapeutic strategies.
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Cougoule, Céline, Véronique Le Cabec, Renaud Poincloux, Talal Al Saati, Jean-Louis Mège, Guillaume Tabouret, Clifford A. Lowell, Nathalie Laviolette-Malirat, and Isabelle Maridonneau-Parini. "Three-dimensional migration of macrophages requires Hck for podosome organization and extracellular matrix proteolysis." Blood 115, no. 7 (February 18, 2010): 1444–52. http://dx.doi.org/10.1182/blood-2009-04-218735.
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Abstract Tissue infiltration of phagocytes exacerbates several human pathologies including chronic inflammations or cancers. However, the mechanisms involved in macrophage migration through interstitial tissues are poorly understood. We investigated the role of Hck, a Src-family kinase involved in the organization of matrix adhesion and degradation structures called podosomes. In Hck−/− mice submitted to peritonitis, we found that macrophages accumulated in interstitial tissues and barely reached the peritoneal cavity. In vitro, 3-dimensional (3D) migration and matrix degradation abilities, 2 protease-dependent properties of bone marrow–derived macrophages (BMDMs), were affected in Hck−/− BMDMs. These macrophages formed few and undersized podosome rosettes and, consequently, had reduced matrix proteolysis operating underneath despite normal expression and activity of matrix metalloproteases. Finally, in fibroblasts unable to infiltrate matrix, ectopic expression of Hck provided the gain–of–3D migration function, which correlated positively with formation of podosome rosettes. In conclusion, spatial organization of podosomes as large rosettes, proteolytic degradation of extracellular matrix, and 3D migration appeared to be functionally linked and regulated by Hck in macrophages. Hck, as the first protein combining a phagocyte-limited expression with a role in 3D migration, could be a target for new anti-inflammatory and antitumor molecules.
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Gu, Qiaoli, Qin Shi, and Huilin Yang. "The Role of TLR and Chemokine in Wear Particle-Induced Aseptic Loosening." Journal of Biomedicine and Biotechnology 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/596870.
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Wear particle-induced periprosthetic osteolysis remains the principal cause of aseptic loosening of orthopaedic implants. Monocytes/macrophages phagocytose wear particles and release cytokines that induce inflammatory response. This response promotes osteoclast differentiation and osteolysis. The precise mechanisms by which wear particles are recognized and induce the accumulation of inflammatory cells in the periprosthetic tissue have not been fully elucidated. Recent studies have shown that toll-like receptors (TLRs) contribute to the cellular interaction with wear particles. Wear particles are recognized by monocytes/macrophages through TLRs coupled with the adaptor protein MyD88. After the initial interaction, wear particles induce both local and systemic migration of monocytes/macrophages to the periprosthetic region. The cellular migration is mediated through chemokines including interleukin-8, macrophage chemotactic protein-1, and macrophage inhibitory protein-1 in the periprosthetic tissues. Interfering with chemokine-receptor axis can inhibit cellular migration and inflammatory response. This paper highlights recent advances in TLR, and chemokine participated in the pathogenesis of aseptic loosening. A comprehensive understanding of the recognition and migration mechanism is critical to the development of measures that prevent wear particle-induced aseptic loosening of orthopaedic implants.
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Gautier, Emmanuel L., Stoyan Ivanov, Philippe Lesnik, and Gwendalyn J. Randolph. "Local apoptosis mediates clearance of macrophages from resolving inflammation in mice." Blood 122, no. 15 (October 10, 2013): 2714–22. http://dx.doi.org/10.1182/blood-2013-01-478206.
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Silva, T. A., V. S. Lara, J. S. Silva, S. H. P. Oliveira, W. T. Butler, and F. Q. Cunha. "Macrophages and Mast Cells Control the Neutrophil Migration Induced by Dentin Proteins." Journal of Dental Research 84, no. 1 (January 2005): 79–83. http://dx.doi.org/10.1177/154405910508400114.
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Dentin sialoprotein (DSP) and dentin phosphoprotein (DPP), the major dentin proteins, have been shown to induce neutrophil migration through release of IL-1β, TNF-α, MIP-2, and KC. However, the sources of these mediators were not determined. Here, the roles of macrophages and mast cells (MC) in dentin-induced neutrophil accumulation were investigated. Peritoneal MC depletion or the enhancement of macrophage population increased DSP- and DPP-induced neutrophil extravasation. Moreover, supernatants from DSP- and DPP-stimulated macrophages caused neutrophil migration. The release of neutrophil chemotactic factor by macrophages was inhibited by dexamethasone or the supernatant of DSP-treated MC. Consistently, dexamethasone and the MC supernatant inhibited the production of IL-1β, TNF-α, and MIP-2 by macrophages. This inhibitory activity of the DSP-stimulated MC was neutralized by anti-IL-4 and anti-IL-10 antibodies. These results indicate that dentin induces the release of the neutrophil chemotactic substance(s) by macrophages, which are down-modulated by MC-derived IL-4 and IL-10.
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Ramakrishnan, Lalita. "Macrophages and Infection Control." Blood 124, no. 21 (December 6, 2014): SCI—9—SCI—9. http://dx.doi.org/10.1182/blood.v124.21.sci-9.sci-9.
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Abstract We have developed a zebrafish model for the study of infection focusing on mycobacteria, which are intracellular pathogens of macrophages, inducing their aggregation into hallmark structures called granulomas. Exploiting the optical transparency and genetic tractability of the developing zebrafish, we can visualize macrophage-pathogen interactions in great detail in live animals and study the consequences of genetic perturbations. We have identified pathways through which macrophages restrict infection and also those that alter macrophage migration, microbicidal capacity, susceptibility to apoptosis and necrosis so as to render them as tools for bacterial expansion. The complex interactions we have uncovered provide new insights into macrophage biology that are relevant not only for tuberculosis and other infectious diseases but also for the pathogenesis of noninfectious inflammatory diseases in which macrophages are increasingly recognized to play an integral role. Disclosures No relevant conflicts of interest to declare.
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Thaler, Barbara, Nagyung Baik, Philipp J. Hohensinner, Johanna Baumgartner, Adelheid Panzenböck, Stefan Stojkovic, Svitlana Demyanets, et al. "Differential expression of Plg-RKT and its effects on migration of proinflammatory monocyte and macrophage subsets." Blood 134, no. 6 (August 8, 2019): 561–67. http://dx.doi.org/10.1182/blood.2018850420.
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Abstract Membrane-bound plasmin is used by immune cells to degrade extracellular matrices, which facilitates migration. The plasminogen receptor Plg-RKT is expressed by immune cells, including monocytes and macrophages. Among monocytes and macrophages, distinct subsets can be distinguished based on cell surface markers and pathophysiological function. We investigated expression of Plg-RKT by monocyte and macrophage subsets and whether potential differential expression might have functional consequences for cell migration. Proinflammatory CD14++CD16+ human monocytes and Ly6Chigh mouse monocytes expressed the highest levels of Plg-RKT and bound significantly more plasminogen compared with the other respective subsets. Proinflammatory human macrophages, generated by polarization with lipopolysaccharide and interferon-γ, showed significantly higher expression of Plg-RKT compared with alternatively activated macrophages, polarized with interleukin-4 and interleukin-13. Directional migration of proinflammatory monocytes was plasmin dependent and was abolished by anti–Plg-RKT monoclonal antibody, ε-amino-caproic acid, aprotinin, and the aminoterminal fragment of urokinase-type plasminogen activator. In an in vivo peritonitis model, significantly less Ly6Chigh monocyte recruitment was observed in Plg-RKT−/− compared with Plg-RKT+/+ mice. Immunohistochemical analysis of human carotid plaques and adipose tissue showed that proinflammatory macrophages also exhibited high levels of Plg-RKT in vivo. Our data demonstrate higher expression of Plg-RKT on proinflammatory monocyte and macrophage subsets that impacts their migratory capacity.
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Abid, Shariq, Elisabeth Marcos, Aurélien Parpaleix, Valérie Amsellem, Marielle Breau, Amal Houssaini, Nora Vienney, et al. "CCR2/CCR5-mediated macrophage–smooth muscle cell crosstalk in pulmonary hypertension." European Respiratory Journal 54, no. 4 (July 18, 2019): 1802308. http://dx.doi.org/10.1183/13993003.02308-2018.
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Macrophages are major players in the pathogenesis of pulmonary arterial hypertension (PAH).To investigate whether lung macrophages and pulmonary-artery smooth muscle cells (PASMCs) collaborate to stimulate PASMC growth and whether the CCL2-CCR2 and CCL5-CCR5 pathways inhibited macrophage–PASMC interactions and PAH development, we used human CCR5-knock-in mice and PASMCs from patients with PAH and controls.Conditioned media from murine M1 or M2 macrophages stimulated PASMC growth. This effect was markedly amplified with conditioned media from M2 macrophage/PASMC co-cultures. CCR2, CCR5, CCL2 and CCL5 were upregulated in macrophage/PASMC co-cultures. Compared to inhibiting either receptor, dual CCR2 and CCR5 inhibition more strongly attenuated the growth-promoting effect of conditioned media from M2-macrophage/PASMC co-cultures. Deleting either CCR2 or CCR5 in macrophages or PASMCs attenuated the growth response. In mice with hypoxia- or SUGEN/hypoxia-induced PH, targeting both CCR2 and CCR5 prevented or reversed PH more efficiently than targeting either receptor alone. Patients with PAH exhibited CCR2 and CCR5 upregulation in PASMCs and perivascular macrophages compared to controls. The PASMC growth-promoting effect of conditioned media from M2-macrophage/PASMC co-cultures was greater when PASMCs from PAH patients were used in the co-cultures or as the target cells and was dependent on CCR2 and CCR5. PASMC migration toward M2-macrophages was greater with PASMCs from PAH patients and was attenuated by blocking CCR2 and CCR5.CCR2 and CCR5 are required for collaboration between macrophages and PASMCs to initiate and amplify PASMC migration and proliferation during PAH development. Dual targeting of CCR2 and CCR5 may hold promise for treating human PAH.
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Van der Hoek, K. H., C. E. Minge, R. J. Norman, and R. L. Robker. "283. Regulated expression of the c-fms receptor characterises distinct ovarian macrophage populations." Reproduction, Fertility and Development 17, no. 9 (2005): 118. http://dx.doi.org/10.1071/srb05abs283.
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Macrophages represent a major immune cell type in reproductive tissues and are thought to regulate multiple aspects of reproduction, including ovarian function. We have previously shown a distinctive phenotype of ovarian thecal macrophages present around the preovulatory follicle, such that secreted cytokines are uniquely regulated within these cells across the oestrus cycle. C-fms is a macrophage-specific gene that encodes the receptor for colony-stimulating factor-1 (CSF-1), and that regulates macrophage proliferation, differentiation and migration, as well as pro-inflammatory responses.1,2 We acquired transgenic mice (from DA Hume, Institute for Molecular Bioscience, University of Queensland) that express green fluorescent protein (GFP) exclusively in macrophages under direction of the c-fms gene promoter.3 In ovaries from these animals we have previously reported that macrophages constitutively positive for macrophage markers, F4/80 and MHCII, exhibited spatially regulated expression of GFP (c-fms); being GFP+ within the stroma surrounding small follicles, particularly atretic follicles, but GFP– in theca surrounding preovulatory follicles and healthy corpora lutea (CL), further reinforcing the concept that these macrophages are not classically activated but have a unique resident phenotype. Further examination of the GFP+ ovarian macrophage population has revealed that the highest levels of GFP expression were in macrophages associated with TUNEL+ regressing CL and, even though CSF-1 typically induces proliferation, the GFP+ macrophages within the regressing CL did not incorporate BrdU label nor express cyclin D1. This indicates that in the murine ovary c-fms expression may not regulate ovarian macrophage proliferation or migration but more likely represents a subset of classically activated ovarian macrophages that are actively differentiating or phagocytically active. (1)Fixe P and Praloran V (1998) Cytokine 10, 32–37.(2)Pixley FJ and Stanley ER (2004) Trends in Cell Biology 14, 628–38.(3)Sasmono RT et al. (2003) Blood 101, 1155–63.
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Huang, Suiqing, Yuan Yue, Kangni Feng, Xiaolin Huang, Huayang Li, Jian Hou, Song Yang, et al. "Conditioned medium from M2b macrophages modulates the proliferation, migration, and apoptosis of pulmonary artery smooth muscle cells by deregulating the PI3K/Akt/FoxO3a pathway." PeerJ 8 (May 5, 2020): e9110. http://dx.doi.org/10.7717/peerj.9110.
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Background Immunity and inflammation are considered to be central features of pulmonary artery hypertension (PAH), in which macrophages are one of the main components of inflammatory cell infiltration around the pulmonary artery. M2b macrophages, which are different from M1 and M2 macrophages, are believed to have immunomodulatory activities and produce little fibrosis. The purpose of this study was to explore the effect of M2b macrophages on pulmonary artery smooth muscle cells (PASMCs) derived from monocrotaline-induced PAH rats. Methods PASMCs were cultured in serum-free medium, the supernatant of M0 macrophages, or the supernatant of M2b macrophages for 24 hours. Then cell proliferation was assessed by cell counting kit-8 and cell migration ability was detected by wound healing and transwell assays. The apoptosis rate of cells was determined by TUNEL staining and annexin V-PE/7-ADD staining. Western blot was used to detect the expression of Bcl-2 family proteins, cleaved caspase-9 and PI3K/Akt/FoxO3a pathway. LY294002 (a specific inhibitor of PI3K) was used to investigate its effect on PASMCs and its relationship with M2b macrophages. Results Conditioned medium from M2b macrophages significantly inhibited the proliferation and migration of PASMCs compared with the control group and M0 macrophage group. Furthermore, conditioned medium from M2b macrophages promote PASMC apoptosis and increased the expression of pro-apoptotic proteins Bax and cleaved caspase-9, inhibited the expression of anti-apoptotic proteins Bcl-2 and Bcl-xl. Finally, conditioned medium from M2b macrophages inhibited the PI3K/Akt/FoxO3a pathway. Inhibition of PI3K/Akt/FoxO3a pathway also significantly inhibit the proliferation, migration, and apoptosis resistance of PASMCs. Conclusion Conditioned medium from M2b macrophages can inhibit the proliferation, migration, and apoptosis resistance of PASMCs, which may be at least partially by deregulating the PI3K/Akt/FoxO3a pathway.
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Tan, Chunyan, Robert Day, Shunzhong Bao, John Turk, and Qingwei David Zhao. "Group VIA Phospholipase A 2 Mediates Enhanced Macrophage Migration in Diabetes Mellitus by Increasing Expression of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4." Arteriosclerosis, Thrombosis, and Vascular Biology 34, no. 4 (April 2014): 768–78. http://dx.doi.org/10.1161/atvbaha.113.302847.
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Objective— We previously demonstrated that nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) mediates increased monocyte priming and chemotaxis under conditions of diabetic metabolic stress, and emerging data indicate that group VIA phospholipase A 2 (iPLA 2 β) also participates in regulating monocyte chemotaxis. Here, we examined relationships between iPLA 2 β expression and Nox4 action in mouse peritoneal macrophages subjected to diabetic metabolic stress. Approach and Results— Increased iPLA 2 β expression and activity were observed in macrophages from low-density lipoprotein receptor knockout mice that were fed a high-fat diet, and this was associated with time-dependent increases in atherosclerotic lesion size and macrophage content. Incubating macrophages with 30 mmol/L D-glucose, 100 μg/mL low-density lipoprotein, or both (D-glucose+low-density lipoprotein) induced a robust increase in iPLA 2 β expression and activity and in cell migration in response to monocyte chemoattractant protein-1. The increases in iPLA 2 β activity and cell migration were prevented by a bromoenol lactone iPLA 2 β suicide inhibitor or an iPLA 2 β antisense oligonucleotide. Incubating macrophages under conditions that mimic diabetic metabolic stress ex vivo resulted in increased Nox4 expression and activity and hydrogen peroxide generation compared with controls. Bromoenol lactone prevented those effects without affecting Nox2 expression. Nox4 inhibition eliminated diabetic metabolic stress–induced acceleration of macrophage migration. Lysophosphatidic acid restored Nox4 expression, hydrogen peroxide generation, and migration to bromoenol lactone–treated cells, and a lysophosphatidic acid receptor antagonist abrogated iPLA 2 β-mediated increases in Nox4 expression. Conclusions— Taken together, these observations identify iPLA 2 β and lysophosphatidic acid derived from its action as critical in regulating macrophage Nox4 activity and migration in the diabetic state in vivo and under similar conditions ex vivo.
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Chen, Lili, and Ming Li. "TMIC-51. GBP1 RECRUITS MACROPHAGES TO PROMOTE GLIOBLASTOMA GROWTH." Neuro-Oncology 21, Supplement_6 (November 2019): vi259. http://dx.doi.org/10.1093/neuonc/noz175.1085.
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Abstract Guanylate binding protein 1 (GBP1) is an interferon-inducible large GTPase which plays a key role in tumor development, but the molecular mechanism is poorly understood. Here we investigated whether GBP1 could influence the tumor microenvironment in glioblastoma, the most common and malignant brain tumor. We found that forced expression of GBP1 in glioblastoma cells induced macrophage polarization toward an M2 phenotype via upregulating Chemokine (C-C motif) ligand 2 (CCL2). CCL2 acted via its receptor C-C chemokine receptor 2 (CCR2) to enhance macrophage cell migration in vitro. The M2 macrophages in turn promoted glioblastoma cell proliferation and migration. The orthotopic mouse model showed that GBP1 recruited M2 macrophages into tumor to promote glioblastoma progression, and targeting CCL2/CCR2 signaling axis with a small molecule inhibitor RS504393 led to decreased macrophage attraction and M2 polarization and a significant tumor growth retardation and prolonged survival of tumor-bearing mice. Clinically, GBP1 expression positively correlated with M2 macrophage numbers and CCL2 expression in glioblastoma. Taken together, our results reveal that GBP1 modulates the tumor immune microenvironment through CCL2 induction to promote glioblastoma infiltrating growth, and targeting tumor-associated macrophages may represent a new therapeutic strategy against glioblastoma.
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Cao, Chunzhang, Daniel A. Lawrence, Dudley K. Strickland, and Li Zhang. "A specific role of integrin Mac-1 in accelerated macrophage efflux to the lymphatics." Blood 106, no. 9 (November 1, 2005): 3234–41. http://dx.doi.org/10.1182/blood-2005-03-1288.
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Abstract In response to injury, monocytes migrate to the site of inflammation, where they differentiate into macrophages and participate in various biologic processes. However, their fate during the resolution of acute inflammation is not fully understood. Here, we show that inflammatory macrophages do not die locally by apoptosis; rather, they migrate across the peritoneal mesothelium to the lymphatics, through which they further migrate to the lymph nodes and to the blood circulation. Macrophage efflux is enhanced considerably on cell activation, and such accelerated macrophage migration is dependent specifically on integrin Mac-1, and can be blocked by addition of its antagonist. Thus, genetic inactivation of Mac-1 in mice inhibits the accelerated macrophage efflux from the inflammatory site to the lymphatics, but it does not compromise the accumulation of blood monocytes into the inflammatory site. Together, our study demonstrates that Mac-1 is involved specifically in the efflux of activated macrophages to the lymphatics, suggesting that Mac-1 may play an important role in the removal of local inflammatory macrophages and in their subsequent migration to the lymph nodes, a process that is critical to the development of the adaptive immunity.
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Hutami, Islamy Rahma, Takashi Izawa, Tsendsuren Khurel-Ochir, Takuma Sakamaki, Akihiko Iwasa, and Eiji Tanaka. "Macrophage Motility in Wound Healing Is Regulated by HIF-1α via S1P Signaling." International Journal of Molecular Sciences 22, no. 16 (August 20, 2021): 8992. http://dx.doi.org/10.3390/ijms22168992.
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Accumulating evidence indicates that the molecular pathways mediating wound healing induce cell migration and localization of cytokines to sites of injury. Macrophages are immune cells that sense and actively respond to disturbances in tissue homeostasis by initiating, and subsequently resolving, inflammation. Hypoxic conditions generated at a wound site also strongly recruit macrophages and affect their function. Hypoxia inducible factor (HIF)-1α is a transcription factor that contributes to both glycolysis and the induction of inflammatory genes, while also being critical for macrophage activation. For the latter, HIF-1α regulates sphingosine 1-phosphate (S1P) to affect the migration, activation, differentiation, and polarization of macrophages. Recently, S1P and HIF-1α have received much attention, and various studies have been performed to investigate their roles in initiating and resolving inflammation via macrophages. It is hypothesized that the HIF-1α/S1P/S1P receptor axis is an important determinant of macrophage function under inflammatory conditions and during disease pathogenesis. Therefore, in this review, biological regulation of monocytes/macrophages in response to circulating HIF-1α is summarized, including signaling by S1P/S1P receptors, which have essential roles in wound healing.
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Hori, Y., S. Sato, J. Yamate, and M. Kurasaki. "Immunohistochemical study of macrophage migration inhibitory factor in rat liver fibrosis induced by thioacetamide." European Journal of Histochemistry 47, no. 4 (June 26, 2009): 317. http://dx.doi.org/10.4081/842.
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Macrophage migration inhibitory factor (MIF) is a molecule known to regulate macrophage accumulation at sites of inflammation. To elucidate the role of MIF in progression of liver fibrosis, the immunohistochemical localization of MIF and macrophages in the liver were examined. Male Wistar rats received thioacetamide (TA) injections (200 mg/kg, i.p.) for 1 or 6 weeks. In biochemical and histological tests, it was confirmed that liver fibrosis was induced. In immunohistochemical analyses, the expression of MIF protein was seen in hepatocytes in the areas extending out from the central veins to the portal tracts. In particular, at 6 weeks, immunoreactivity was detected in degenerated hepatocytes adjacent to the fibrotic areas but hardly observed in the fibrotic areas. On the other hand, a number of exudate macrophages stained by antibody ED1 were seen in the areas from the central veins to the portal tracts at 1 week and in the fibrotic areas at 6 weeks. Macrophages also showed a significant increase in number as compared with controls. These results revealed that there was a close relationship between the appearance of MIF expression and ED1-positive exudate macrophages in degenerated hepatocytes during the progression of TA-induced liver fibrosis.
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Chen, Peiwen, Hao Zuo, Hu Xiong, Matthew J. Kolar, Qian Chu, Alan Saghatelian, Daniel J. Siegwart, and Yihong Wan. "Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis." Proceedings of the National Academy of Sciences 114, no. 3 (January 3, 2017): 580–85. http://dx.doi.org/10.1073/pnas.1614035114.
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Macrophages are prominent immune cells in the tumor microenvironment that exert potent effects on cancer metastasis. However, the signals and receivers for the tumor–macrophage communication remain enigmatic. Here, we show that G protein-coupled receptor 132 (Gpr132) functions as a key macrophage sensor of the rising lactate in the acidic tumor milieu to mediate the reciprocal interaction between cancer cells and macrophages during breast cancer metastasis. Lactate activates macrophage Gpr132 to promote the alternatively activated macrophage (M2)-like phenotype, which, in turn, facilitates cancer cell adhesion, migration, and invasion. Consequently, Gpr132 deletion reduces M2 macrophages and impedes breast cancer lung metastasis in mice. Clinically, Gpr132 expression positively correlates with M2 macrophages, metastasis, and poor prognosis in patients with breast cancer. These findings uncover the lactate-Gpr132 axis as a driver of breast cancer metastasis by stimulating tumor–macrophage interplay, and reveal potential new therapeutic targets for breast cancer treatment.
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Zhang, Pengjun, Jianmei Sun, Caihong Liang, Bingjie Gu, Yang Xu, Hongying Lu, Bo Cao, and Hao Xu. "lncRNA IGHCγ1 Acts as a ceRNA to Regulate Macrophage Inflammation via the miR-6891-3p/TLR4 Axis in Osteoarthritis." Mediators of Inflammation 2020 (January 17, 2020): 1–11. http://dx.doi.org/10.1155/2020/9743037.
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Accumulating data have implicated that long noncoding RNA (lncRNA) plays an important role in osteoarthritis (OA), which may function as a competitive endogenous RNA (ceRNA) of microRNAs (miRNAs). lncRNA IGHCγ1 has been demonstrated to regulate inflammation and autoimmunity. Nonetheless, the altering effect of IGHCγ1 in OA remains unclear. This study is aimed at investigating the mechanism and function of lncRNA IGHCγ1 in OA. CCK-8, EdU, and transwell assays were used to estimate macrophage proliferation and migration. Fluorescence in situ hybridization (FISH) was performed to estimate the local expression of lncRNA IGHCγ1 in macrophages. Luciferase reporter assay was adopted to validate the ceRNA role of IGHCγ1 as miRNA sponge. lncRNA IGHCγ1 was primarily localized in macrophage cytoplasm and upregulated in OA. miR-6891-3p inhibited macrophage proliferation, migration, and inflammatory response by targeting TLR4, while lncRNA IGHCγ1 promoted TLR4 expression by functioning as a ceRNA for miR-6891-3p through the NF-κB signal in macrophages. This study strongly supports that lncRNA IGHCγ1 regulates inflammatory response via regulating the miR-6891-3p/TLR4/NF-κB axis in macrophages.
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Park, Young Mi, Judith A. Drazba, Amit Vasanji, Thomas Egelhoff, Maria Febbraio, and Roy L. Silverstein. "Oxidized LDL/CD36 interaction induces loss of cell polarity and inhibits macrophage locomotion." Molecular Biology of the Cell 23, no. 16 (August 15, 2012): 3057–68. http://dx.doi.org/10.1091/mbc.e11-12-1051.
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Cell polarization is essential for migration and the exploratory function of leukocytes. However, the mechanism by which cells maintain polarity or how cells revert to the immobilized state by gaining cellular symmetry is not clear. Previously we showed that interaction between oxidized low-density lipoprotein (oxLDL) and CD36 inhibits macrophage migration; in the current study we tested the hypothesis that oxLDL/CD36-induced inhibition of migration is the result of intracellular signals that regulate cell polarity. Live cell imaging of macrophages showed that oxLDL actuated retraction of macrophage front end lamellipodia and induced loss of cell polarity. Cd36 null and macrophages null for Vav, a guanine nucleotide exchange factor (GEF), did not show this effect. These findings were caused by Rac-mediated inhibition of nonmuscle myosin II, a cell polarity determinant. OxLDL induced dephosphorylation of myosin regulatory light chain (MRLC) by increasing the activity of Rac. Six-thioguanine triphosphate (6-thio-GTP), which inhibits Vav-mediated activation of Rac, abrogated the effect of oxLDL. Activation of the Vav-Rac-myosin II pathway by oxidant stress may induce trapping of macrophages at sites of chronic inflammation such as atherosclerotic plaque.
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Kadomoto, Suguru, Kouji Izumi, Kaoru Hiratsuka, Taito Nakano, Renato Naito, Tomoyuki Makino, Hiroaki Iwamoto, et al. "Tumor-Associated Macrophages Induce Migration of Renal Cell Carcinoma Cells via Activation of the CCL20-CCR6 Axis." Cancers 12, no. 1 (December 30, 2019): 89. http://dx.doi.org/10.3390/cancers12010089.
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This study investigated tumor-associated macrophages activity in the microenvironment of renal cell carcinoma. Via a co-culture with macrophage-like cells differentiated from human monocyte cell line THP-1 and U937 cells, the migration ability of ACHN and Caki-1 cells, which are human renal cell carcinoma cell line cells, was significantly increased, as was the epithelial–mesenchymal transition change. A chemokine array identified the CCL20-CCR6 axis as a concentration-dependent signal in ACHN and Caki-1 cell migration. Akt in the ACHN and Caki-1 cells was activated by macrophage-like cells, and the CCL20 neutralizing antibody suppressed migration ability, epithelial–mesenchymal transition, and Akt phosphorylation in the ACHN and Caki-1 cells. Akt inhibitor AZD5363 also decreased the epithelial–mesenchymal transition change and migration ability in the ACHN and Caki-1 cells. In 42 renal cell carcinoma tissues, patients with CCR6 and macrophage infiltration indicated poor prognoses. In the tumor microenvironment of renal cell carcinoma, cancer cells are activated by CCL20 secreted by tumor-associated macrophages through Akt activation, followed by epithelial–mesenchymal transition and an acquired migration ability. Thus, inhibition of the CCL20-CCR6 axis may be a potential therapeutic strategy for renal cell carcinoma.