scholarly journals Cell-intrinsic IL4R alpha independence of large intestinal RELMα+ Ym1+ macrophages

2020 ◽  
Author(s):  
Ruth Forman ◽  
Larisa Logunova ◽  
Hannah Smith ◽  
Kelly Wemyss ◽  
Iris Mair ◽  
...  
Keyword(s):  
Large Intestine ◽  
Post Infection ◽  
Macrophage Activation ◽  
Intestinal Inflammation ◽  
Infection Model ◽  
Unexpected Finding ◽  
Trichuris Muris ◽  
Anti Inflammatory ◽  
Inflammatory Macrophages

ABSTRACTThe balance of pro-inflammatory and anti-inflammatory macrophages is critically important in enabling the development and resolution of inflammatory responses. Anti-inflammatory macrophages have been shown to be activated by IL4 and/or IL13 via the IL4Rα. In the context of type 2 immunity, anti-inflammatory macrophages have been defined by the expression of the signature markers RELMα, CD206 and Ym1, associated with activation of macrophages via the IL4Rα. Despite a breadth of inflammatory pathologies associated with the large intestine, many of which feature unbalanced macrophage activation states, little is known about how large intestinal macrophages are activated. Here, we address this important knowledge gap by using a Trichuris muris infection model of resolving type 2 intestinal inflammation, in combination with transgenic mice (IL4Rαfl/fl.CX3CR1Cre) and IL4Rα-deficient/wild-type mixed bone marrow chimaeras. These models allowed us to interrogate the role of IL4/IL13 in macrophage activation driven by inflammation of the large intestine. We make the unexpected finding that education of large intestinal macrophages towards a RELMα and Ym1 expressing cell type during type 2 inflammation, does not require IL4Rα expression on macrophages. Thus, upregulation of RELMα and Ym1 post infection is independent of macrophage IL4Rα expression. Further, this independence is maintained even when the mice are treated with anti-IFNγ antibody to create a strongly polarised Th2 environment. In contrast to RELMα and Ym1, PD-L2 expression on macrophages post infection was dependent on IL4Rα signalling in the macrophages. These data challenge existing paradigms, evidencing that expression of RELMα and Ym1 by macrophages, typically regarded as having anti-inflammatory functions, do not always rely on IL4/IL13.

scholarly journals Investigating the importance of B cells and antibodies during Trichuris muris infection using the IgMi mouse

2020 ◽  
Vol 98 (9) ◽  
pp. 1301-1317
Author(s):  
Rinal Sahputra ◽  
Emma A Murphy ◽  
Ruth Forman ◽  
Iris Mair ◽  
Muhammad Z. H. Fadlullah ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Post Infection ◽  
Cell Biology ◽  
Low Dose ◽  
Cell Function ◽  
Intestinal Inflammation ◽  
High Dose ◽  
List Type ◽  
Trichuris Muris

Abstract The IgMi mouse has normal B cell development; its B cells express an IgM B cell receptor but cannot class switch or secrete antibody. Thus, the IgMi mouse offers a model system by which to dissect out antibody-dependent and antibody-independent B cell function. Here, we provide the first detailed characterisation of the IgMi mouse post-Trichuris muris (T. muris) infection, describing expulsion phenotype, cytokine production, gut pathology and changes in T regulatory cells, T follicular helper cells and germinal centre B cells, in addition to RNA sequencing (RNA seq) analyses of wild-type littermates (WT) and mutant B cells prior to and post infection. IgMi mice were susceptible to a high-dose infection, with reduced Th2 cytokines and elevated B cell-derived IL-10 in mesenteric lymph nodes (MLN) compared to controls. A low-dose infection regime revealed IgMi mice to have significantly more apoptotic cells in the gut compared to WT mice, but no change in intestinal inflammation. IL-10 levels were again elevated. Collectively, this study showcases the potential of the IgMi mouse as a tool for understanding B cell biology and suggests that the B cell plays both antibody-dependent and antibody-independent roles post high- and low-dose T. muris infection. Key messages During a high-dose T. muris infection, B cells are important in maintaining the Th1/Th2 balance in the MLN through an antibody-independent mechanism. High levels of IL-10 in the MLN early post-infection, and the presence of IL-10-producing B cells, correlates with susceptibility to T. muris infection. B cells maintain gut homeostasis during chronic T. muris infection via an antibody-dependent mechanism.

scholarly journals Low-Dose Intestinal Trichuris muris Infection Alters the Lung Immune Microenvironment and Can Suppress Allergic Airway Inflammation

2015 ◽  
Vol 84 (2) ◽  
pp. 491-501 ◽  
Author(s):  
Alistair L. Chenery ◽  
Frann Antignano ◽  
Kyle Burrows ◽  
Sebastian Scheer ◽  
Georgia Perona-Wright ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Cross Talk ◽  
Low Dose ◽  
Intestinal Inflammation ◽  
Allergic Airway Inflammation ◽  
Interleukin 10 ◽  
Th1 Cell ◽  
Trichuris Muris ◽  
Airway Pathology

Immunological cross talk between mucosal tissues such as the intestine and the lung is poorly defined during homeostasis and disease. Here, we show that a low-dose infection with the intestinally restricted helminth parasiteTrichuris murisresults in the production of Th1 cell-dependent gamma interferon (IFN-γ) and myeloid cell-derived interleukin-10 (IL-10) in the lung without causing overt airway pathology. This cross-mucosal immune response in the lung inhibits the development of papain-induced allergic airway inflammation, an innate cell-mediated type 2 airway inflammatory disease. Thus, we identify convergent and nonredundant roles of adaptive and innate immunity in mediating cross-mucosal suppression of type 2 airway inflammation during low-dose helminth-induced intestinal inflammation. These results provide further insight in identifying novel intersecting immune pathways elicited by gut-to-lung mucosal cross talk.

scholarly journals Metformin Triggers Apoptosis and Induction of the G0/G1 Switch 2 Gene in Macrophages

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1437
Author(s):  
Xuming Hu ◽  
Huan Luo ◽  
Chunfeng Dou ◽  
Xujing Chen ◽  
Yi Huang ◽  
...  
Keyword(s):  
Marker Genes ◽  
M2 Macrophage ◽  
Dependent Manner ◽  
M1 Macrophages ◽  
Inflammatory Mechanism ◽  
Anti Inflammatory ◽  
Induced Apoptosis ◽  
Inflammatory Macrophages ◽  
Dose Dependent

Metformin is a widely used antidiabetic drug for the treatment of type 2 diabetes and has been recently demonstrated to possess anti-inflammatory properties via AMPK-mediated modulation of M2 macrophage activation. However, the anti-inflammatory mechanisms of metformin on inflammatory macrophages are still not fully elucidated. In this study, we found that metformin induced apoptosis in macrophages. In particular, metformin induced apoptosis of M1 macrophages, based on M1 marker genes in apoptotic macrophages. Next, we comprehensively screened metformin-responsive genes in macrophages by RNA-seq and focused on the extrinsic apoptotic signaling pathway. The G0/G1 switch 2 gene (G0S2) was robustly up-regulated by metformin in macrophages. Overexpression of G0S2 significantly induced apoptosis of macrophages in a dose-dependent manner and blunted the function of the crucial anti-apoptotic gene Bcl-2, which was significantly reduced by metformin. These findings show that metformin promoted apoptosis of macrophages, especially M1 macrophages, via G0S2 induction and provides a novel anti-inflammatory mechanism of metformin through induction of macrophage apoptosis.

scholarly journals Enteric glial cells favour accumulation of anti-inflammatory macrophages during the resolution of muscularis inflammation

2021 ◽  
Author(s):  
Michelle Stakenborg ◽  
Saeed Abdurahiman ◽  
Veronica De Simone ◽  
Gera Goverse ◽  
Nathalie Stakenborg ◽  
...  
Keyword(s):  
Glial Cells ◽  
Intestinal Inflammation ◽  
Mononuclear Phagocyte ◽  
Inflammatory Factors ◽  
Monocyte Differentiation ◽  
Enteric Glial Cells ◽  
Monocyte Recruitment ◽  
Microenvironmental Factors ◽  
Anti Inflammatory ◽  
Inflammatory Macrophages

Objective: Monocyte-derived macrophages (Mϕs) are crucial regulators during muscularis inflammation. However, it is unclear which microenvironmental factors are responsible for monocyte recruitment and neurotrophic Mϕ differentiation in this paradigm. Here, we investigate Mϕ heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue protective Mϕs. Design: Single cell RNA sequencing was performed on immune cells from the muscularis of wild-type and CCR2-/- mice at different timepoints after muscularis inflammation. CX3CR1GFP/+ and CX3CR1CreERT2 R26YFP mice were analyzed by flow cytometry and immunofluorescence. The transcriptome of enteric glial cells (EGCs) was investigated using PLPCreERT2 Rpl22HA mice. In addition, we assessed the effect of supernatant from neurosphere-derived EGCs on monocyte differentiation based on the expression of pro- and anti-inflammatory factors. Results: Muscularis inflammation induced marked alterations in mononuclear phagocyte populations associated with a rapid infiltration of Ly6c+ monocytes that locally acquired unique transcriptional states. Trajectory inference analysis revealed two main pro-resolving Mϕs subpopulations during the resolution of muscularis inflammation, i.e. Cd206+ MhcIIhi and Timp2+ MhcIIlo Mϕs, which were both derived from CCR2+ monocytes. Interestingly, we found that EGCs were able to sense damage to the muscularis to stimulate monocyte recruitment and differentiation towards pro-resolving Mϕs via CCL2 and CSF1, respectively. Conclusion: Our study provides a comprehensive insight into pro-resolving Mϕ differentiation and their regulators during muscularis inflammation. We deepened our understanding in the interaction between EGCs and Mϕs, thereby highlighting pro-resolving Mϕ differentiation as a potential novel therapeutic strategy for the treatment of intestinal inflammation.

scholarly journals A219 PROTECTIVE EFFECTS OF AKKERMANSIA MUCINIPHILA ON INTESTINAL BARRIER FUNCTION AND INFLAMMATION

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 93-94
Author(s):  
J Grondin ◽  
H Wang ◽  
S Haq ◽  
E Y Kwon ◽  
M Surette ◽  
...  
Keyword(s):  
Goblet Cell ◽  
Worm Burden ◽  
Intestinal Inflammation ◽  
Protective Role ◽  
Protective Effects ◽  
Trichuris Muris ◽  
Barrier Integrity ◽  
Akkermansia Muciniphila ◽  
Anti Inflammatory

Abstract Background Akkermansia muciniphila, an anaerobic gram-negative bacteria, accounts for ~3% of human gut microbiota. Despite its mucolytic nature, A. muciniphila has been shown to stimulate mucin production, enhance anti-inflammatory regulatory T cell proliferation and improve gut barrier integrity. Interestingly, an inverse relationship has been established between A. muciniphila and several disease states including inflammatory bowel disease (IBD) suggesting it may have protective and anti-inflammatory effects. However, the precise role and mechanism of A. muciniphila in the pathogenesis of colitis remains unknown. Thus, we hypothesize that A. muciniphila may induce protective effects on intestinal inflammation by influencing host immune response and epithelial barrier integrity. Aims (1) To investigate the protective role of A. muciniphila in intestinal inflammation in a chemically induced model of IBD and (2) to investigate the protective role of A. muciniphila in intestinal inflammation and host defense in a model of enteric parasitic infection. Methods Colitis was induced in germ-free C57BL/6 mice with 2.5% dextran sulphate sodium (DSS) after treatment with either C57BL/6 wild-type (WT) cecal contents or WT cecal contents supplemented with A. muciniphila. Colitis severity was assessed by disease activity index (DAI), macroscopic and histological scores, myeloperoxidase (MPO) assay and cytokine expression. In addition, colitis was induced by Trichuris muris, an intestinal nematode, following treatment with A. muciniphila. Post-infection, the severity of intestinal inflammation was assessed by worm burden, goblet cell staining, cytokines analysis, MPO activity and Muc2 expression. Microbial composition was assessed by 16s rRNA gene sequencing. Results In preliminary studies, mice treated with A. muciniphila and administered DSS for 5 days yielded a significant decrease in DAI, macroscopic scoring, and MPO values compared with controls. IL-10 was also elevated in mice receiving A. muciniphila. Groups receiving A. muciniphila in the T. muris model trended toward decreased worm burden, IL-4, IL-13, as well as increased levels of IL-10, goblet cell expression, and Muc2 and Muc5ac expression. A significant decrease in MPO activity was also observed in the group receiving the A. muciniphila-supplemented gavage. Microbial analysis indicated that 3 weeks post-gavage Akkermansia levels were significantly elevated in groups receiving the A. muciniphila-supplemented WT cecal contents versus WT alone. This significance was maintained post-T. muris infection. Conclusions These findings suggest that A. muciniphila may have a protective role in the context of intestinal inflammation. This research has the potential to fuel the development of novel treatments by utilizing this protective role in IBD. Funding Agencies CIHR

Abstract 649: PARP14 and PARP9 Are Novel Regulators of Macrophage Activation

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Hiroshi Iwata ◽  
Piero Ricchiuto ◽  
Takuya Hara ◽  
Amitabh Sharma ◽  
Alex Mojcher ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Macrophage Polarization ◽  
Vascular Diseases ◽  
Interleukin 4 ◽  
Human Macrophage ◽  
Physical Interaction ◽  
Anti Inflammatory ◽  
Inflammatory Macrophages

Purpose: A microenvironment dominant in pro-inflammatory macrophages (“M1”) and lacking anti-inflammatory macrophages (“M2”) may promote vascular diseases. We explored and validated key regulators of such macrophage polarization. Methods and Results: Using global proteomic analysis and bioinformatics, we examined the changes in the proteomes of mouse and human macrophage cell lines (RAW264.7; THP-1) in response to interferon gamma (IFNγ) or interleukin 4 (IL-4) for M1 or M2 polarization, respectively. Among 5816 proteins in RAW264.7 and 4723 in THP-1, data filtering and clustering identified poly(ADP-ribose) polymerase 14 (PARP14) and 9 (PARP9) as candidates for key regulators of macrophage polarization, which increase in M1 and decrease in M2 condition. siRNA silencing of PARP14 in macrophages induced M1 genes TNF-α, IL-1β and iNOS, while decreased M2 markers Arg1 and MRC1, indicating that PARP14 suppresses pro-inflammatory macrophage activation and promotes anti-inflammatory polarization. PARP14 silencing induced STAT1 phosphorylation and reduced STAT6 phosphorylation, suggesting their roles in the underlying signaling mechanisms. In contrast, PARP9 silencing decreased M1 markers, as well as phosphorylation of STAT1. Of interest, a direct physical interaction between PARP14 and PARP9 was also demonstrated. In vivo evidence supported these in vitro findings. Macrophages of PARP14-deficient mice expressed markedly higher levels of M1 genes and lower levels M2 markers. PARP14 deficiency accelerated lesion development after mechanical injury in femoral arteries. Conclusions: PARP14 and PARP9 regulate macrophage activation, offering novel therapeutic targets for vascular diseases.

scholarly journals Consumption of transglycosylated starch down-regulates expression of mucosal innate immune response genes in the large intestine using a pig model

2018 ◽  
Vol 119 (12) ◽  
pp. 1366-1377 ◽  
Author(s):  
Barbara U. Metzler-Zebeli ◽  
Monica A. Newman ◽  
Dietmar Grüll ◽  
Qendrim Zebeli
Keyword(s):  
Large Intestine ◽  
Barrier Function ◽  
Intestinal Inflammation ◽  
Least Squares Regression ◽  
Toll Like Receptor 4 ◽  
Expression Of Genes ◽  
Mucin 2 ◽  
Anti Inflammatory ◽  
Induced Changes ◽  
Inflammatory Signalling

AbstractBenefits of resistant starch (RS) consumption on host physiology encompass microbial activity-derived attenuation of intestinal inflammation. However, little is known about anti-inflammatory properties of RS of type 4. This study compared the effects of transglycosylated starch (TGS) consumption on the jejunal barrier function and expression of genes related to inflammation, barrier function and the mucosal defence in jejunum, ileum, caecum and colon of pigs. Moreover, interactions of TGS-induced alterations in bacterial metabolites and composition with host mucosal responses were assessed using sparse partial least squares regression and relevance network analysis. Intestinal samples were collected after pigs (n 8/diet; 4 months of age) were fed the experimental diets for 10 d. Consumption of TGS did not modify jejunal barrier function and gene expression. By contrast, TGS down-regulated the caecal expression of zonula occludens-1 and mucin 2 and of genes within the toll-like receptor 4 and NF-κB pro-inflammatory signalling cascade. Relevance networks revealed a microbiome signature on ileal, caecal and colonic mucosal signalling as TGS-derived changes in bacterial genera and fermentation acids, such as propionic acid, correlated with the differently expressed genes in ileum, caecum and colon of pigs. In conclusion, the present findings suggest certain anti-inflammatory capabilities of TGS by down-regulating the expression of pro-inflammatory pathways in the caecal mucosa, which seems to be mediated, at least in part, by TGS-induced changes in microbial action in the large intestine.

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