Journal articles on the topic 'Thioglycollate-elicited murine peritonitis model'
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1
LaFleur, Andrew M., Nicholas W. Lukacs, Steven L. Kunkel, and Akihiro Matsukawa. "Role of CC chemokine CCL6/C10 as a monocyte chemoattractant in a murine acute peritonitis." Mediators of Inflammation 13, no. 5-6 (2004): 349–55. http://dx.doi.org/10.1080/09629350400014172.
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THE aim of this study was to determine the role of CC chemokine CCL6/C10 in acute inflammation. Intraperitoneal injection of thioglycollate increased peritoneal CCL6, which peaked at 4 h and remained elevated at 48 h. Neutralization of CCL6 significantly inhibited the macrophage infiltration (34-48% reduction), but not other cell types, without decreasing the other CC chemokines known to attract monocytes/macrophages. CCL6 was expressed in peripheral eosinophils and elicited macrophages, but not in elicited neutrophils. Peritoneal CCL6 level was not decreased in granulocyte-depleted mice where eosinophil influx was significantly impaired. Thus, CCL6 appears to contribute to the macrophage infiltration that is independent of other CC chemokines. Eosinophils pre-store CCL6, but do not release CCL6 in the peritoneum in this model of inflammation.
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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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Mohammed, Bassem M., Bernard J. Fisher, Quoc K. Huynh, Dayanjan S. Wijesinghe, Charles E. Chalfant, Donald F. Brophy, Alpha A. Fowler III, and Ramesh Natarajan. "Resolution of Sterile Inflammation: Role for Vitamin C." Mediators of Inflammation 2014 (2014): 1–15. http://dx.doi.org/10.1155/2014/173403.
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Introduction. Macrophage reprogramming is vital for resolution of acute inflammation. Parenteral vitamin C (VitC) attenuates proinflammatory states in murine and human sepsis. However information about the mechanism by which VitC regulates resolution of inflammation is limited.Methods. To examine whether physiological levels of VitC modulate resolution of inflammation, we used transgenic mice lacking L-gulono-γ-lactone oxidase. VitC sufficient/deficient mice were subjected to a thioglycollate-elicited peritonitis model of sterile inflammation. Some VitC deficient mice received daily parenteral VitC (200 mg/kg) for 3 or 5 days following thioglycollate infusion. Peritoneal macrophages harvested on day 3 or day 5 were examined for intracellular VitC levels, pro- and anti-inflammatory protein and lipid mediators, mitochondrial function, and response to lipopolysaccharide (LPS). The THP-1 cell line was used to determine the modulatory activities of VitC in activated human macrophages.Results. VitC deficiency significantly delayed resolution of inflammation and generated an exaggerated proinflammatory response toin vitroLPS stimulation. VitC sufficiency andin vivoVitC supplementation restored macrophage phenotype and function in VitC deficient mice. VitC loading of THP-1 macrophages attenuated LPS-induced proinflammatory responses.Conclusion. VitC sufficiency favorably modulates macrophage function.In vivoorin vitroVitC supplementation restores macrophage phenotype and function leading to timely resolution of inflammation.
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Bogen, S., J. Pak, M. Garifallou, X. Deng, and W. A. Muller. "Monoclonal antibody to murine PECAM-1 (CD31) blocks acute inflammation in vivo." Journal of Experimental Medicine 179, no. 3 (March 1, 1994): 1059–64. http://dx.doi.org/10.1084/jem.179.3.1059.
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A murine model of peritonitis was used to test the role of platelet/endothelial cell adhesion molecule 1 (PECAM-1/CD31) in acute inflammation. A monoclonal antibody (mAb) specific for murine PECAM-1 injected intravenously 4 h before the intraperitoneal injection of thioglycollate broth blocked leukocyte emigration into the peritoneal cavity for up to 48 h. This block was particularly evident for neutrophils. Control mAb, including one that bound to murine CD18 without blocking its function, failed to block emigration when used at the same or higher concentrations. The decreased emigration seen with the anti-PECAM-1 antibody was not due to neutropenia or neutrophil sequestration in the lung, spleen, or other organs; peripheral blood leukocyte counts were not diminished in these mice. In the mesenteric venules of the mice treated with anti-PECAM-1 mAb, leukocytes were frequently seen in association with the luminal surface of the vessel, but did not appear to emigrate. Thus, the requirement for PECAM-1 in the transendothelial migration of leukocytes previously seen in an in vitro model holds true in this in vivo model of acute inflammation.
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Chih Chen, Yung, Jennifer Rivera, Melissa Fitzgerald, Christian Hausding, Ya-Lan Ying, Xiaowei Wang, Krassimira Todorova, Soren Hayrabedyan, Eytan R. Barnea, and Karlheinz Peter. "PreImplantation factor prevents atherosclerosis via its immunomodulatory effects without affecting serum lipids." Thrombosis and Haemostasis 115, no. 05 (2016): 1010–24. http://dx.doi.org/10.1160/th15-08-0640.
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SummaryPreImplantation factor (PIF) is a 15-amino acid peptide endogenously secreted by viable embryos, regulating/enabling maternal (host) acceptance/tolerance to the “invading” embryo (allograft) all-while preserving maternal immunity to fight infections. Such attributes make PIF a potential therapeutic agent for chronic inflammatory diseases. We investigated whether PIF’s immunomodulatory properties prevent progression of atherosclerosis in the hyper-cholesterolaemic ApoEdeficient murine model. Male, high-fat diet fed, ApoE-deficient (ApoE-/-) mice were administered either PBS, scrambled PIF (0.3–3 mg/kg) or PIF (0.3–3 mg/kg) for seven weeks. After treatment, PIF (3 mg/kg)-treated ApoE-/- mice displayed significantly reduced atherosclerosis lesion burden in the aortic sinus and aortic arch, without any effect on lipid profile. PIF also caused a significant reduction in infiltration of macrophages, decreased expression of pro-inflammatory adhesion molecules, cytokines and chemokines in the plaque, and reduced circulating IFN-γ levels. PIF preferentially binds to monocytes/neutrophils. In vitro, PIF attenuated monocyte migration (MCP-1-induced chemotaxis assay) and in vivo in LPS peritonitis model. Also PIF prevented leukocyte extravasation (peritonitis thioglycollate-induced model), demonstrating that PIF exerts its effect in part by modulation of monocyte function. Inhibition of the potassium channel KCNAB3 (Kv1.3) and of the insulin degrading enzyme (IDE) was demonstrated as potential mechanism of PIF’s immunomodulatory effects. In conclusion, PIF regulates/lowers inflammation and prevents atherosclerosis development without affecting circulating lipids. Overall our findings establish PIF as a strong immunomodulatory drug candidate for atherosclerosis therapy.Supplementary Material to this article is available online at www.thrombosis-online.com.
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Ramos, Carroll L., Eric J. Kunkel, Michael B. Lawrence, Unsu Jung, Dietmar Vestweber, Roland Bosse, Kim W. McIntyre, et al. "Differential Effect of E-Selectin Antibodies on Neutrophil Rolling and Recruitment to Inflammatory Sites." Blood 89, no. 8 (April 15, 1997): 3009–18. http://dx.doi.org/10.1182/blood.v89.8.3009.
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Abstract The selectins are inducible adhesion molecules critically important for the inflammatory response. We investigate here the functional effects of three monoclonal antibodies (MoAbs) raised against murine E-selectin (9A9, 10E6, and 10E9.6) on neutrophil recruitment in vivo, leukocyte rolling and circulating leukocyte concentrations in vivo, and adhesion of myeloid cells to E-selectin transfectants and recombinant E-selectin–IgG fusion protein in vitro. MoAbs 9A9 and 10E6 map to the lectin and epidermal growth factor (EGF)-like domains of murine E-selectin, whereas 10E9.6 binds to the consensus repeat region. 10E9.6 blocked neutrophil recruitment in a model of thioglycollate-induced peritonitis in Balb/c mice by more than 90% but had no effect in C57BL/6 mice. 9A9 and 10E6 blocked neutrophil recruitment in this assay only when combined with a P-selectin antibody, 5H1. Neither 9A9 nor 10E9.6 alone blocked leukocyte rolling in tumor necrosis factor-α–treated venules of Balb/c mice, but 9A9 almost completely inhibited leukocyte rolling when combined with the function-blocking murine P-selectin MoAb, RB40.34. In contrast, 10E9.6 had no effect on leukocyte rolling in RB40.34-treated Balb/c or C57BL/6 mice. 10E9.6 did not affect adhesion of myeloid cells to E-selectin transfectants or attachment, rolling, and detachment of myeloid cells to murine E-selectin–IgG fusion protein. However, adhesion was completely blocked in the same assays by 9A9. Taken together, these results indicate that E-selectin serves a function, other than rolling, that appears to be critically important for neutrophil recruitment to inflammatory sites in Balb/c mice.
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Wengner, Antje M., Simon C. Pitchford, Rebecca C. Furze, and Sara M. Rankin. "The coordinated action of G-CSF and ELR + CXC chemokines in neutrophil mobilization during acute inflammation." Blood 111, no. 1 (January 1, 2008): 42–49. http://dx.doi.org/10.1182/blood-2007-07-099648.
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In this study, we have identified a unique combinatorial effect of the chemokines KC/MIP-2 and the cytokine granulocyte colony-stimulating factor (G-CSF) with respect to the rapid mobilization of neutrophils from the bone marrow in a model of acute peritonitis. At 2 hours following an intraperitoneal injection of thioglycollate, there was a 4.5-fold increase in blood neutrophil numbers, which was inhibited 84% and 72% by prior administration of blocking mAbs against either the chemokines KC/MIP-2 or G-CSF, respectively. An intraperitoneal injection of G-CSF acted remotely to stimulate neutrophil mobilization, but did not elicit recruitment into the peritoneum. Further, in vitro G-CSF was neither chemotactic nor chemokinetic for murine neutrophils, and had no priming effect on chemotaxis stimulated by chemokines. Here, we show that, in vitro and in vivo, G-CSF induces neutrophil mobilization by disrupting their SDF-1α–mediated retention in the bone marrow. Using an in situ perfusion system of the mouse femoral bone marrow to directly assess mobilization, KC and G-CSF mobilized 6.8 × 106 and 5.4 × 106 neutrophils, respectively, while the infusion of KC and G-CSF together mobilized 19.5 × 106 neutrophils, indicating that these factors act cooperatively with respect to neutrophil mobilization.
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Accarias, Solène, Clémence Genthon, David Rengel, Séverine Boullier, Gilles Foucras, and Guillaume Tabouret. "Single-cell analysis reveals new subset markers of murine peritoneal macrophages and highlights macrophage dynamics upon Staphylococcus aureus peritonitis." Innate Immunity 22, no. 5 (May 24, 2016): 382–92. http://dx.doi.org/10.1177/1753425916651330.
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Resident macrophages play a central role in maintaining tissue homeostasis and immune surveillance. Here, we used single cell-based qPCR coupled with flow cytometry analysis to further define the phenotypes of large and small resident peritoneal macrophages (LPMs and SPMs, respectively) in mice. We demonstrated that the expression of Cxcl13, IfngR1, Fizz-1 and Mrc-1 clearly distinguished between LPMs and SPMs subsets. Using these markers, the dynamics of peritoneal macrophages in a Staphylococcus aureus-induced peritonitis model were analyzed. We found that S. aureus infection triggers a massive macrophage disappearance reaction in both subsets. Thereafter, inflammatory monocytes rapidly infiltrated the cavity and differentiated to replenish the SPMs. Although phenotypically indistinguishable from resident SPMs by flow cytometry, newly recruited SPMs had a different pattern of gene expression dominated by M2 markers combined with M1 associated features (inos expression). Interestingly, S. aureus elicited SPMs showed a robust expression of Cxcl13, suggesting that these cells may endorse the role of depleted LPMs and contribute to restoring peritoneal homeostasis. These data provide information on both resident and recruited macrophages dynamics upon S. aureus infection and demonstrate that single-cell phenotyping is a promising and highly valuable approach to unraveling macrophage diversity and plasticity.
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Massa, Christine, Emma Braine, Jason Lenzo, Amanda Turner, Kerrie Way, John Hamilton, Andrew Cook, and Ross Vlahos. "The effect of tissue type-plasminogen activator deletion and associated fibrin(ogen) deposition on macrophage localization in peritoneal inflammation." Thrombosis and Haemostasis 95, no. 04 (2006): 659–67. http://dx.doi.org/10.1160/th05-06-0405.
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SummaryThere are two plasminogen activators (PAs), urokinase type-PA (u-PA) and tissue type-PA (t-PA). While u-PA is considered to be involved in cellular migration and tissue remodeling and t-PA in fibrinolysis, this distinction is not always clear-cut. With the use of u-PA and t-PA gene deficient mice (u-PA-/and t-PA-/mice, respectively) we have assessed the role of each PA in acute peritonitis. The cellular infiltrate in both thioglycolateand antigen-induced peritoneal exudates was unaffected in u-PA-/mice; in contrast, in t-PA-/mice, the macrophage numbers, particularly of the Mac-1hi population, in the peritoneal cavity by day4 were significantly reduced compared to wild-type mice. However, examination of the peritoneal wall revealed in fact increased numbers of macrophages adhering on/in the cavity lining at all time points studied; in addition, increased fibrin(ogen) staining was observed for these mice. The reduced macrophage numbers in the peritoneal cavities of t-PA-/mice could be increased by administration of plasmin or t-PA prior to harvesting the thioglycolate-elicited exudates. These results suggest that t-PA and not u-PA is the PA controlling fibrinolysis in murine peritonitis. In its absence macrophages adhere to the accumulated fibrin(ogen) on/in the cavity wall lining, most likely via Mac-1 binding, thus affecting migration into and/or out of the peritoneal cavity. They also highlight the need to examine both the peritoneal cavity and wall in order to monitor accurately the extent of a peritoneal inflammatory reaction. Peritoneal inflammation in t-PA-/mice represents a useful model to study the progression of intra-abdominal adhesions during surgery and clinical peritonitis.
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Ajuebor, Maureen N., Anuk M. Das, László Virág, Roderick J. Flower, Csaba Szabó, and Mauro Perretti. "Role of Resident Peritoneal Macrophages and Mast Cells in Chemokine Production and Neutrophil Migration in Acute Inflammation: Evidence for an Inhibitory Loop Involving Endogenous IL-10." Journal of Immunology 162, no. 3 (February 1, 1999): 1685–91. http://dx.doi.org/10.4049/jimmunol.162.3.1685.
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Abstract The roles played by resident macrophages (Mφ) and mast cells (MCs) in polymorphonuclear leukocyte (PMN) accumulation and chemokine production within the mouse peritoneal cavity in response to administration of zymosan (0.2 and 1 mg), LPS (1 mg/kg), and thioglycolate (0.5 ml of a 3% suspension) were investigated. A marked reduction (>95%) in intact MC numbers was obtained by pretreatment with the MC activator compound 48/80, whereas resident Mφ were greatly diminished (>85%) by a 3-day treatment with liposomes encapsulating the cytotoxic drug dichloromethylene-bisphosphonate. No modulation of thioglycolate-induced inflammation was seen with either pretreatment. Removal of either MCs or Mφ attenuated LPS-induced PMN extravasation without affecting the levels of the chemokines murine monocyte chemoattractant protein-1 and KC measured in the lavage fluids. In contrast, MC depletion inhibited PMN accumulation and murine monocyte chemoattractant protein-1 and KC production in the zymosan peritonitis model. Removal of Mφ augmented the accumulation of PMN elicited by the latter stimulus. This was due to an inhibitory action of Mφ-derived IL-10 because there was 1) a time-dependent release of IL-10 in the zymosan exudates; 2) a reduction in IL-10 levels following Mφ, but not MC, depletion; and 3) an increased PMN influx and chemokine production in IL-10 knockout mice. In conclusion, we propose a stimulus-dependent role of resident MCs in chemokine production and the existence of a regulatory loop between endogenous IL-10 and the chemokine-mediated cellular component of acute inflammation.
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Lam, Derek, Devon Harris, and Zhenyu Qin. "Inflammatory Mediator Profiling Reveals Immune Properties of Chemotactic Gradients and Macrophage Mediator Production Inhibition during Thioglycollate Elicited Peritoneal Inflammation." Mediators of Inflammation 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/931562.
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Understanding of spatiotemporal profiling of inflammatory mediators and their associations with MΦ accumulation is crucial to elucidate the complex immune properties. Here, we used murine thioglycollate elicited peritonitis to determine concentrations of 23 inflammatory mediators in peritoneal exudates and plasma before (day 0) and after (days 1 and 3) thioglycollate administration to peritoneal cavities; these mediators included TNF-α, FGF-9, IFN-γ, IP-10, RANTES, IL-1α, IL-6, IL-7, IL-10, IL-11, IL-12p70, IL-17A, lymphotactin, OSM, KC/GRO, SCF, MIP-1β, MIP-2, TIMP-1, VEGF-A, MCP-1, MCP-3, and MCP-5. Our results showed that concentrations of most mediators in exudates and plasma reached peak levels on day 1 and were significantly reduced on day 3. Conversely, MΦnumbers started to increase on day 1 and reached peak levels on day 3. Moreover, LPS treatmentin vitrosignificantly induced mediator productions in cell culture media and lysates from MΦisolated on day 3. Our results also showed that on day 0, concentrations of many mediators in plasma were higher than those in exudates, whereas on day 1, the trend was reversed. Overall, the findings from thioglycollate elicited peritonitis reveal that reversible chemotactic gradients between peritoneal exudates and blood exist in basal and inflamed conditions and the inflammatory mediator productionin vivois disassociated with macrophage accumulation during inflammation resolution.
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Weiel, J. E., D. O. Adams, and T. A. Hamilton. "Biochemical models of gamma-interferon action: altered expression of transferrin receptors on murine peritoneal macrophages after treatment in vitro with PMA or A23187." Journal of Immunology 134, no. 1 (January 1, 1985): 293–98. http://dx.doi.org/10.4049/jimmunol.134.1.293.
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Abstract The number of transferrin receptors in thioglycollate-elicited murine peritoneal macrophages is markedly depressed after exposure to murine gamma-interferon (IFN gamma) in vitro. This change has been used as a model system to study the molecular and cellular mechanisms of IFN gamma signal transduction. We observed that the downshift of the transferrin receptor could be mimicked by exposure to the calcium ionophore (A23187) or the potent tumor promoter, phorbol 12-myristate 13-acetate (PMA). Saturation binding studies on thioglycollate (TG)-elicited peritoneal macrophages after exposure to A23187 or PMA showed the reduced expression of transferrin binding activity attributable to a decrease in the total number of cellular transferrin receptors and not an alteration in receptor-ligand affinity, in agreement with previous results obtained after exposure to IFN gamma. The loss of transferrin receptors in response to A23187 or PMA was dose dependent, and the kinetics of the change were identical to those observed with IFN gamma treatment. Phorbol 12,13-dibutyrate or 4-beta-phorbol 12,13-didecanoate, both biologically active phorbol esters, also induced reduced expression of transferrin receptors, whereas nonesterified phorbol or 4-alpha-phorbol 12,13-didecanoate, an inactive phorbol ester, had no effect on transferrin receptor expression. Finally, PMA and A23187, when used together, acted cooperatively to modulate transferrin receptor expression when both agents were present at subthreshold concentrations. These results, taken together, suggest that elevation of intracellular Ca++ levels and/or stimulation of protein kinase C are involved in the response of macrophages to IFN gamma.
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Lee, Daniel D., Alexandra Hochstetler, Christina Murphy, Chinn-Woan Lowe, and Margaret A. Schwarz. "A distinct transcriptional profile in response to endothelial monocyte activating polypeptide II is partially mediated by JAK-STAT3 in murine macrophages." American Journal of Physiology-Cell Physiology 317, no. 3 (September 1, 2019): C449—C456. http://dx.doi.org/10.1152/ajpcell.00277.2018.
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Macrophages are important responders to environmental changes such as secreted factors. Among the secreted factors in injured tissues, the highly conserved endothelial monocyte activating polypeptide II (EMAP II) has been characterized to limit vessel formation, to be locally expressed near sites of injury labeling it a “find-me” signal, and to recruit macrophages and neutrophils. The molecular mechanisms mediated by EMAP II within macrophages once they are recruited are unknown. In this study, using a model of partially activated, recruited thioglycollate-elicited peritoneal macrophages, a transient, transcription profile of key functional genes in macrophages exposed to EMAP II was characterized. We found that EMAP II-mediated changes were elicited mainly through signal transducer and activator of transcription 3 (STAT3) as evidenced by increased Y705 phosphorylation and changes in activity and upstream of it, Janus associated kinase (JAK)1/2 upstream. Both inhibition of JAK1/2 and knockdown of Stat3 abrogated a subset of genes that are upregulated by EMAP II. Our results identify a rapid EMAP II-mediated STAT3 activation that coincides with altered pro- and anti-inflammatory gene expression in macrophages.
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Thomas, Graham D., Dominik Rückerl, Benjamin H. Maskrey, Phillip D. Whitfield, Mark L. Blaxter, and Judith E. Allen. "The biology of nematode- and IL4Rα-dependent murine macrophage polarization in vivo as defined by RNA-Seq and targeted lipidomics." Blood 120, no. 25 (December 13, 2012): e93-e104. http://dx.doi.org/10.1182/blood-2012-07-442640.
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Abstract Alternatively activated macrophages (AAMφ) are a major component of the response to helminth infection; however, their functions remain poorly defined. To better understand the helminth-induced AAMφ phenotype, we performed a systems-level analysis of in vivo derived AAMφ using an established mouse model. With next-generation RNA sequencing, we characterized the transcriptomes of peritoneal macrophages from BALB/c and IL4Rα−/− mice elicited by the nematode Brugia malayi, or via intraperitoneal thioglycollate injection. We defined expression profiles of AAMφ-associated cytokines, chemokines, and their receptors, providing evidence that AAMφ contribute toward recruitment and maintenance of eosinophilia. Pathway analysis highlighted complement as a potential AAMφ-effector function. Up-regulated mitochondrial genes support in vitro evidence associating mitochondrial metabolism with alternative activation. We mapped macrophage transcription start sites, defining over-represented cis-regulatory motifs within AAMφ-associated promoters. These included the binding site for PPAR transcription factors, which maintain mitochondrial metabolism. Surprisingly PPARγ, implicated in the maintenance of AAMφ, was down-regulated on infection. PPARδ expression, however, was maintained. To explain how PPAR-mediated transcriptional activation could be maintained, we used lipidomics to quantify AAMφ-derived eicosanoids, potential PPAR ligands. We identified the PPARδ ligand PGI2 as the most abundant AAMφ-derived eicosanoid and propose a PGI2-PPARδ axis maintains AAMφ during B malayi implantation.
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Hunter, Cheryl, Tejas B. Kadakia, Dianne Cooper, Mauro Perretti, Richard C. Schwartz, and Simon B. Brown. "Selective Inhibitors of Kv11.1 Regulate IL-6 Expression by Macrophages in Response to TLR/IL-1R Ligands." Scientific World JOURNAL 10 (2010): 1580–96. http://dx.doi.org/10.1100/tsw.2010.155.
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The mechanism by which the platelet-endothelial cell adhesion molecule PECAM-1 regulates leukodiapedesis, vascular endothelial integrity, and proinflammatory cytokine expressionin vivois not known. We recently identified PECAM-1 as a negative regulator of Kv11.1, a specific voltage-gated potassium channel that functioned in human macrophages to reset a resting membrane potential following depolarization. We demonstrate here that dofetilide (DOF), a selective inhibitor of the Kv11.1 current, had a profound inhibitory effect on neutrophil recruitment in mice following TLR/IL-1R–elicited peritonitis or intrascrotal injection of IL-1β, but had no effect on responses seen with TNFα. Furthermore, inhibitors of Kv11.1 (DOF, E4031, and astemizole), but not Kv1.3 (margatoxin), suppressed the expression of IL-6 and MCP-1 cytokines by murine resident peritoneal macrophages, while again having no effect on TNFα. In contrast, IL-6 expression by peritoneal mesothelial cells was unaffected. Using murine P388 cells, which lack endogenous C/EBPβexpression and are unresponsive to LPS for the expression of both IL-6 and MCP-1, we observed that DOF inhibited LPS-induced expression of IL-6 mRNA following ectopic expression of wild-type C/EBPβ, but not a serine-64 point mutant. Finally, DOF inhibited the constitutive activation of cdk2 in murine peritoneal macrophages; cdk2 is known to phosphorylate C/EBPβ at serine-64. Taken together, our results implicate a potential role for Kv11.1 in regulating cdk2 and C/EBPβ activity, where robust transactivation of both IL-6 and MCP-1 transcription is known to be dependent on serine-64 of C/EBPβ. Our data might also explain the altered phenotypes displayed by PECAM-1 knockout mice in several disease models.
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Warren, M. K., and S. N. Vogel. "Bone marrow-derived macrophages: development and regulation of differentiation markers by colony-stimulating factor and interferons." Journal of Immunology 134, no. 2 (February 1, 1985): 982–89. http://dx.doi.org/10.4049/jimmunol.134.2.982.
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Abstract To investigate the role of specific cytokines in the development of the fully mature macrophage, we have employed murine bone marrow cells that were grown in the presence of CSF-1, a colony-stimulating factor that has been shown to induce the proliferation and differentiation of macrophages from their precursor cells. The CSF-1 employed in these studies was partially purified to ensure removal of contaminating interferon (IFN) from the preparations. After 1 to 2 wk in the presence of the partially purified CSF-1, the adherent macrophages were removed from flasks enzymatically and were recultured at known densities in the absence of CSF-1. Cell surface antigens (Mac-1 and Ia) and Fc receptor capacity (as assessed by Fc-mediated phagocytosis) were examined as markers of macrophage differentiation. Basal levels of Fc receptor capacity and Mac-1 antigen were markedly influenced by exposure to CSF-1, and appear to be modulated by CSF-induced, macrophage-derived IFN. When the bone marrow-derived macrophages were exposed to exogenous IFN in the absence of CSF-1, they proved to be extremely inducible with respect to Fc-mediated phagocytosis (IFN-beta and rIFN-gamma) and Ia antigen expression (rIFN-gamma) when compared with thioglycollate-elicited macrophages. Thus, macrophage growth factors, such as CSF-1, promote macrophage maturation by inducing the production of autostimulatory signals, such as macrophage-derived IFN. In addition, exogenous cytokine stimuli, such as IFN-gamma, further amplify the differentiative potential of these cells. Bone marrow-derived macrophages, propagated under well-defined conditions and never exposed to eliciting agents, provide a powerful model for studying the role of cytokines, such as CSF-1 and IFN, in the differentiative pathway of macrophages.
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Fukui, Saeko, Shoichi Fukui, Stijn Van Bruggen, Lai Shi, Casey E. Sheehy, Long Chu, and Denisa D. Wagner. "NLRP3 inflammasome activation in neutrophils directs early inflammatory response in murine peritonitis." Scientific Reports 12, no. 1 (December 9, 2022). http://dx.doi.org/10.1038/s41598-022-25176-4.
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AbstractNLR family pyrin domain containing 3 (NLRP3) inflammasome mediates caspase-1-dependent processing of inflammatory cytokines such as IL-1β, an essential endothelial activator, and contributes to the pathology of inflammatory diseases. To evaluate the role of NLRP3 in neutrophils in endothelial activation, which is still elusive, we used the thioglycollate-induced peritonitis model characterized by an early neutrophil influx, on Nlrp3−/− and Nlrp3+/+ mice. Nlrp3−/− mice recruited fewer neutrophils than Nlrp3+/+ into the peritoneum and showed lower IL-1β in peritoneal lavage fluid. The higher production of IL-1β in Nlrp3+/+ was neutrophil-dependent as neutrophil depletion prevented the IL-1β production. The Nlrp3+/+ neutrophils collected from the peritoneal fluid formed significantly more filaments (specks) than Nlrp3−/− neutrophils of ASC (apoptosis-associated speck-like protein containing a caspase activating and recruitment domain), a readout for inflammasome activation. Intravital microscopy revealed that leukocytes rolled significantly slower in Nlrp3+/+ venules than in Nlrp3−/−. Nlrp3−/− endothelial cells isolated from mesenteric vessels demonstrated a lower percentage of P-selectin-positive cells with lower intensity of surface P-selectin expression than the Nlrp3+/+ endothelial cells evaluated by flow cytometry. We conclude that neutrophils orchestrate acute thioglycollate-induced peritonitis by producing IL-1β in an NLRP3-dependent manner. This increases endothelial P-selectin expression and leukocyte transmigration.
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Miao, Zhenhua, Linda S. Ertl, Bin Zhao, Yu Wang, Dale Newland, Yibin Zeng, Jeffrey McMahon, et al. "P0973ALLOSTERIC C-C CHEMOKINE RECEPTOR TYPE 2 (CCR2) INHIBITION IMPROVES RENAL FUNCTION IN A MURINE MODEL OF DIABETIC NEPHROPATHY." Nephrology Dialysis Transplantation 35, Supplement_3 (June 1, 2020). http://dx.doi.org/10.1093/ndt/gfaa142.p0973.
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Abstract Background and Aims Diabetic nephropathy (DN) is a syndrome characterized by pathological levels of proteinuria, glomerular lesions and reduction in the glomerular filtration rate (GFR) in diabetic patients. Several lines of evidence support a role of CCR2 in the pathogenesis of DN. Recent studies have demonstrated that existing small molecule CCR2 antagonists can be placed in two classes, distinguished by their interaction with one of two distinct binding sites on CCR2: an extracellular site for which antagonists compete directly with native ligands (the orthosteric site), or an intracellular allosteric binding site. To better understand the functional differences between these antagonists we compared an example of each class in a murine model of DN. Our results revealed that the allosteric, but not the orthosteric CCR2 inhibitors ameliorated the proteinuria and improved glomerular histopathology in this model of DN. Method We used db/db mice to model DN. Several structurally distinct CCR2 inhibitors with that bind to either the allosteric (CCR2-RA-[R] and CCX872) or orthosteric (MK-0812 and CCX598) sites were compared. Pharmacokinetic (PK) properties and renal functional parameters were assessed, including trough drug levels and proteinuria (urinary albumin excretion rate UAER; urine albumin creatinine ratio UACR). Histopathology and electron microscopy (EM) were performed to assess any potential tissue-protective effects of the antagonists. Results Both the allosteric inhibitors (CCR2-RA-[R] and CCX872) and the orthosteric inhibitors (MK-0812 and CCX598) were potent CCR2 antagonists with desirable PK in mouse in so far as both classes effectively blocked CCR2-mediated monocyte migration into the peritoneal cavity in the thioglycollate-induced peritonitis model. At comparable drug coverage levels, CCR2-RA-[R] and CCX872 rapidly and significantly reduced UAER/UACR (CCX872: 70 % at day 7 vs vehicle, p<0.0001; and 60 % at day 14 vs vehicle, p=0.001; CCR2-RA-[R]: 60 % at day 7 vs vehicle, p=0.0001; and 58 % at day 14 vs vehicle, p=0.005), but MK-0812 and CCX598 did not exhibit proteinuria lowering effect. Histological parameters including glomerular injury and glomerular basement membrane (GBM) thickness were also improved after CCX872 treatment in db/db mice. Conclusion Allosteric antagonists of CCR2 provide significant and rapid renal protection in the db/db murine model of DN, as evidenced by improvements in renal function and histological parameters, while potent orthosteric CCR2 antagonists were not effective in the model. Our data suggest that targeting the effectiveness of CCR2 antagonists in DN are directly dependent on binding to the allosteric site of CCR2.
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Martínez-Aguilar, Rocío, Salvador Romero-Pinedo, M. José Ruiz-Magaña, Enrique G. Olivares, Carmen Ruiz-Ruiz, and Ana C. Abadía-Molina. "Menstrual blood-derived stromal cells modulate functional properties of mouse and human macrophages." Scientific Reports 10, no. 1 (December 2020). http://dx.doi.org/10.1038/s41598-020-78423-x.
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AbstractMenstrual blood-derived stromal cells (MenSCs) are emerging as a strong candidate for cell-based therapies due to their immunomodulatory properties. However, their direct impact on innate immune populations remains elusive. Since macrophages play a key role in the onset and development of inflammation, understanding MenSCs implication in the functional properties of these cells is required to refine their clinical effects during the treatment of inflammatory disorders. In this study, we assessed the effects that MenSCs had on the recruitment of macrophages and other innate immune cells in two mouse models of acute inflammation, a thioglycollate (TGC)-elicited peritonitis model and a monobacterial sepsis model. We found that, in the TGC model, MenSCs injection reduced the percentage of macrophages recruited to the peritoneum and promoted the generation of peritoneal immune cell aggregates. In the sepsis model, MenSCs exacerbated infection by diminishing the recruitment of macrophages and neutrophils to the site of infection and inducing defective bacterial clearance. Additional in vitro studies confirmed that co-culture with MenSCs impaired macrophage bactericidal properties, affecting bacterial killing and the production of reactive oxygen intermediates. Our findings suggest that MenSCs modulate the macrophage population and that this modulation must be taken into consideration when it comes to future clinical applications.