scholarly journals Macrophage dysfunction initiates colitis during weaning of infant mice lacking the interleukin-10 receptor

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Naresh S Redhu ◽  
Vasudevan Bakthavatchalu ◽  
Evan A Conaway ◽  
Dror S Shouval ◽  
Amy Tsou ◽  
...  
Keyword(s):  
Infant Development ◽  
Intestinal Inflammation ◽  
Interleukin 10 ◽  
Postnatal Period ◽  
Macrophage Function ◽  
Murine Colitis ◽  
Macrophage Depletion ◽  
Macrophage Dysfunction ◽  
Inflammatory Bowel ◽  
Deficient Mice

Infants with defects in the interleukin 10 receptor (IL10R) develop very early onset inflammatory bowel disease. Whether IL10R regulates lamina propria macrophage function during infant development in mice and whether macrophage-intrinsic IL10R signaling is required to prevent colitis in infancy is unknown. Here we show that although signs of colitis are absent in IL10R-deficient mice during the first two weeks of life, intestinal inflammation and macrophage dysfunction begin during the third week of life, concomitant with weaning and accompanying diversification of the intestinal microbiota. However, IL10R did not directly regulate the microbial ecology during infant development. Interestingly, macrophage depletion with clodronate inhibited the development of colitis, while the absence of IL10R specifically on macrophages sensitized infant mice to the development of colitis. These results indicate that IL10R-mediated regulation of macrophage function during the early postnatal period is indispensable for preventing the development of murine colitis.

scholarly journals Studies on the Interleukin-10 Gene in Animal Models of Colitis

2001 ◽  
Vol 15 (8) ◽  
pp. 557-558
Author(s):  
Hugh J Freeman
Keyword(s):  
Inflammatory Bowel Disease ◽  
Animal Models ◽  
Bowel Disease ◽  
Inflammatory Process ◽  
Intestinal Inflammation ◽  
Therapeutic Potential ◽  
Interleukin 10 ◽  
Necrosis Factor Alpha ◽  
Inflammatory Bowel ◽  
Deficient Mice

Cytokines play a role in the inflammatory process in colitis and may have therapeutic potential. Interleukin-10 (IL-10) has both immunomodulatory and anti-inflammatory properties. IL-10-deficient mice develop intestinal inflammation with increased tissue levels of other cytokines, including tumour necrosis factor-alpha. In patients with inflammatory bowel disease, impaired IL-10 production by lamina propria T cells occurs and human recombinant IL-10 improves clinical parameters in inflammatory bowel disease (eg, Crohn's disease). There seem to be conflicting results in differing animal models, and the timing of administration of IL-10 relative to onset of colitis may be critical, possibly due to rapid clearance of IL-10. Interestingly, in IL-10 gene-deficient mice raised in germ-free conditions, the intestinal inflammatory changes normally observed in conventional nongerm-free conditions are not detected, suggesting a role for luminal bacteria in the pathogenesis of the inflammatory process.

scholarly journals Probiotic Lactobacillus spp. Diminish Helicobacter hepaticus-Induced Inflammatory Bowel Disease in Interleukin-10-Deficient Mice

2005 ◽  
Vol 73 (2) ◽  
pp. 912-920 ◽  
Author(s):  
Jeremy A. Peña ◽  
Arlin B. Rogers ◽  
Zhongming Ge ◽  
Vivian Ng ◽  
Sandra Y. Li ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Real Time ◽  
Bowel Disease ◽  
Interleukin 10 ◽  
Helicobacter Hepaticus ◽  
Murine Colitis ◽  
Tnf Α ◽  
Inflammatory Bowel ◽  
Deficient Mice ◽  
Colitis Model

ABSTRACT Clinical and experimental evidence has demonstrated the potential role of probiotics in the prevention or treatment of inflammatory bowel disease. Probiotic clones with direct immunomodulatory activity may have anti-inflammatory effects in the intestine. We investigated the roles of tumor necrosis factor alpha (TNF-α)-inhibitory Lactobacillus clones with a pathogen-induced murine colitis model. Murine-derived probiotic lactobacilli were selected in vitro for their ability to inhibit TNF-α secretion by Helicobacter hepaticus-stimulated macrophages. Interleukin-10 (IL-10)-deficient mice were treated with probiotic Lactobacillus reuteri in combination with Lactobacillus paracasei and then challenged with H. hepaticus. Ten weeks postinoculation, the severity of typhlocolitis was assessed by histologic examination of the cecocolic region. Intestinal proinflammatory cytokine responses were evaluated by real-time quantitative reverse transcriptase PCR and immunoassays, and the quantities of intestinal H. hepaticus were evaluated by real-time PCR. Intestinal colonization by TNF-α-inhibitory lactobacilli reduced intestinal inflammation in H. hepaticus-challenged IL-10-deficient mice despite similar quantities of H. hepaticus in cocolonized animals. Proinflammatory colonic cytokine (TNF-α and IL-12) levels were lowered in Lactobacillus-treated animals. In this H. hepaticus-challenged IL-10-deficient murine colitis model, lactobacilli demonstrated probiotic effects by direct modulation of mucosal inflammatory responses.

scholarly journals Extracellular vesicles package dsDNA to aggravate Crohn’s disease by activating the STING pathway

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Fan Zhao ◽  
Tao Zheng ◽  
Wenbin Gong ◽  
Jie Wu ◽  
Haohao Xie ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Extracellular Vesicles ◽  
Intestinal Inflammation ◽  
Therapeutic Effects ◽  
Murine Colitis ◽  
Sting Pathway ◽  
Deficient Mice

AbstractCrohn’s disease (CD) is an intestinal immune-dysfunctional disease. Extracellular vesicles (EVs) are membrane-enclosed particles full of functional molecules, e.g., nuclear acids. Recently, EVs have been shown to participate in the development of CD by realizing intercellular communication among intestinal cells. However, the role of EVs carrying double-strand DNA (dsDNA) shed from sites of intestinal inflammation in CD has not been investigated. Here we isolated EVs from the plasma or colon lavage of murine colitis and CD patients. The level of exosomal dsDNA, including mtDNA and nDNA, significantly increased in murine colitis and active human CD, and was positively correlated with the disease activity. Moreover, the activation of the STING pathway was verified in CD. EVs from the plasma of active human CD triggered STING activation in macrophages in vitro. EVs from LPS-damaged colon epithelial cells were also shown to raise inflammation in macrophages via activating the STING pathway, but the effect disappeared after the removal of exosomal dsDNA. These findings were further confirmed in STING-deficient mice and macrophages. STING deficiency significantly ameliorated colitis. Besides, potential therapeutic effects of GW4869, an inhibitor of EVs release were assessed. The application of GW4869 successfully ameliorated murine colitis by inhibiting STING activation. In conclusion, exosomal dsDNA was found to promote intestinal inflammation via activating the STING pathway in macrophages and act as a potential mechanistic biomarker and therapeutic target of CD.

scholarly journals Phosphatase Shp2 exacerbates intestinal inflammation by disrupting macrophage responsiveness to interleukin-10

2019 ◽  
Vol 216 (2) ◽  
pp. 337-349 ◽  
Author(s):  
Peng Xiao ◽  
Huilun Zhang ◽  
Yu Zhang ◽  
Mingzhu Zheng ◽  
Rongbei Liu ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Interleukin 10 ◽  
Blood Monocytes ◽  
Stat3 Signaling ◽  
Tnf Α ◽  
Mouse Macrophages ◽  
Inflammatory Bowel ◽  
Anti Inflammatory ◽  
Further Development

Inflammatory cytokines produced by activated macrophages largely contribute to the pathological signs of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is the predominant anti-inflammatory cytokine in the intestine, and its therapeutic efficacy for IBD has been clinically tested. Nevertheless, how the function of IL-10 is regulated in the intestinal microenvironment remains unknown, which largely hinders the further development of IL-10–based therapeutic strategies. Here, we found that the expression of phosphatase Shp2 was increased in colonic macrophages and blood monocytes from IBD patients compared with those from healthy controls. Shp2 deficiency in macrophages protects mice from colitis and colitis-driven colon cancer. Mechanistically, Shp2 disrupts IL-10–STAT3 signaling and its dependent anti-inflammatory response in human and mouse macrophages. Furthermore, a Shp2-inducing role of TNF-α is unveiled in our study. Collectively, our work identifies Shp2 as a detrimental factor for intestinal immune homeostasis and hopefully will be helpful in the future exploitation of IL-10 immunotherapy for IBD.

scholarly journals IL-10 Treatment Is Associated with Prohibitin Expression in the Crohn’s Disease Intestinal Fibrosis Mouse Model

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
C. Yuan ◽  
W.-X. Chen ◽  
J.-S. Zhu ◽  
N.-W. Chen ◽  
Y.-M. Lu ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Quantitative Polymerase Chain Reaction ◽  
Interleukin 10 ◽  
Colon Tissue ◽  
Intestinal Fibrosis ◽  
Murine Colitis ◽  
Inflammatory Bowel

Prohibitin, which can inhibit oxidative stress and mitochondrial dysfunction, has been shown to have significant anti-inflammatory activities. Here, we investigate the effects of altering prohibitin levels in affected tissues in the interleukin-10 knockout (IL-10KO) mouse model with intestinal fibrosis. The aim of this study is to investigate the effects of IL-10 on prohibitin and the role of prohibitin in intestinal fibrosis of murine colitis. After the mice were treated with IL-10, prohibitin expression and localization were evaluated in IL-10KO and wild-type (WT, 129/SvEv) mice. The colon tissue was then investigated and the potential pathogenic molecular mechanisms were further studied. Fluorescence-based quantitative polymerase chain reaction (FQ-PCR) and immunohistochemistry assays revealed a significant upregulation of prohibitin with IL-10 treatment. Furthermore, IL-10 decreases inflammatory cytokines and TGF-β1 in the IL-10KO model of Crohn’s disease and demonstrates a promising trend in decreasing tissue fibrosis. In conclusion, we hypothesize that IL-10 treatment is associated with increased prohibitin and would decrease inflammation and fibrosis in an animal model of Crohn’s disease. Interestingly, prohibitin may be a potential target for intestinal fibrosis associated with inflammatory bowel disease (IBD).

scholarly journals Enhanced susceptibility to chemically induced colitis caused by excessive endosomal TLR signaling in LRBA-deficient mice

2019 ◽  
Vol 116 (23) ◽  
pp. 11380-11389 ◽  
Author(s):  
Kuan-wen Wang ◽  
Xiaoming Zhan ◽  
William McAlpine ◽  
Zhao Zhang ◽  
Jin Huk Choi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Intestinal Inflammation ◽  
Type I ◽  
Induced Mutations ◽  
Tlr Signaling ◽  
Nonsense Mutations ◽  
Chemically Induced ◽  
Inflammatory Bowel ◽  
Deficient Mice ◽  
Stimulation Of

LPS-responsive beige-like anchor (LRBA) protein deficiency in humans causes immune dysregulation resulting in autoimmunity, inflammatory bowel disease (IBD), hypogammaglobulinemia, regulatory T (Treg) cell defects, and B cell functional defects, but the cellular and molecular mechanisms responsible are incompletely understood. In an ongoing forward genetic screen forN-ethyl-N-nitrosourea (ENU)-induced mutations that increase susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice, we identified two nonsense mutations inLrba. Although Tregcells have been a main focus in LRBA research to date, we found that dendritic cells (DCs) contribute significantly to DSS-induced intestinal inflammation in LRBA-deficient mice.Lrba−/−DCs exhibited excessive IRF3/7- and PI3K/mTORC1-dependent signaling and type I IFN production in response to the stimulation of the Toll-like receptors (TLRs) 3, TLR7, and TLR9. Substantial reductions in cytokine expression and sensitivity to DSS in LRBA-deficient mice were caused by knockout ofUnc93b1, a chaperone necessary for trafficking of TLR3, TLR7, and TLR9 to endosomes. Our data support a function for LRBA in limiting endosomal TLR signaling and consequent intestinal inflammation.

scholarly journals Attenuation of Intestinal Inflammation in Interleukin-10-Deficient Mice Infected with Citrobacter rodentium

2014 ◽  
Vol 82 (5) ◽  
pp. 1949-1958 ◽  
Author(s):  
Sara M. Dann ◽  
Christine Le ◽  
Barun K. Choudhury ◽  
Houpu Liu ◽  
Omar Saldarriaga ◽  
...  
Keyword(s):  
Immune Responses ◽  
Intestinal Inflammation ◽  
Acute Infection ◽  
Interleukin 10 ◽  
Mucosal Inflammation ◽  
Immune Functions ◽  
Citrobacter Rodentium ◽  
Microbial Infection ◽  
Content Type ◽  
Deficient Mice

ABSTRACTInterleukin-10 (IL-10) curtails immune responses to microbial infection and autoantigens and contributes to intestinal immune homeostasis, yet administration of IL-10 has not been effective at attenuating chronic intestinal inflammatory conditions, suggesting that its immune functions may be context dependent. To gain a broader understanding of the importance of IL-10 in controlling mucosal immune responses to infectious challenges, we employed the murine attaching and effacing pathogenCitrobacter rodentium, which colonizes primarily the surfaces of the cecum and colon and causes transient mucosal inflammation driven by Th17 and Th1 T helper cells. Infection induced macrophage and dendritic cell production of IL-10, which diminished antibacterial host defenses, because IL-10-deficient mice cleared infection faster than wild-type controls. In parallel, the mice had less acute infection-associated colitis and resolved it more rapidly than controls. Importantly, transientC. rodentiuminfection protected IL-10-deficient mice against the later development of spontaneous colitis that normally occurs with aging in these mice. Genome-wide expression studies revealed that IL-10 deficiency was associated with downregulation of proinflammatory pathways but increased expression of the anti-inflammatory cytokine IL-27 in response to infection. IL-27 was found to suppressin vitroTh17 and, to a lesser degree, Th1 differentiation independent of IL-10. Furthermore, neutralization of IL-27 resulted in more severe colitis in infected IL-10-deficient mice. Together, these findings indicate that IL-10 is dispensable for resolvingC. rodentium-associated colitis and further suggest that IL-27 may be a critical factor for controlling intestinal inflammation and Th17 and Th1 development by IL-10-independent mechanisms.

Natural Colonization with Helicobacter species and the Development of Inflammatory Bowel Disease in Interleukin-10-deficient Mice

Helicobacter ◽  
2005 ◽  
Vol 10 (3) ◽  
pp. 223-230 ◽  
Author(s):  
Li Zhang ◽  
Stephen J. Danon ◽  
Martin Grehan ◽  
Vivian Chan ◽  
Adrian Lee ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Interleukin 10 ◽  
Inflammatory Bowel ◽  
Deficient Mice

scholarly journals 15-Deoxy-△12,14-Prostaglandin J2 Promotes Resolution of Experimentally Induced Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Wonki Kim ◽  
Jeong-Hoon Jang ◽  
Xiancai Zhong ◽  
Hyungseok Seo ◽  
Young-Joon Surh
Keyword(s):  
Arachidonic Acid ◽  
Colonic Mucosa ◽  
Molecular Mechanisms ◽  
Intestinal Inflammation ◽  
M1 Macrophages ◽  
Murine Colitis ◽  
Stat3 Phosphorylation ◽  
Prostaglandin D Synthase ◽  
Inflammatory Bowel ◽  
Experimentally Induced

Uncontrolled macrophage functions cause failure to resolve gut inflammation and has been implicated in the pathogenesis of inflammatory bowel disease (IBD). 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of endogenous lipid mediators formed from arachidonic acid during the inflammatory process, has been reported to terminate inflammation. However, the pro-resolving effect of 15d-PGJ2 on intestinal inflammation and underlying molecular mechanisms remain largely unknown. In the present study, we examined the effects of 15d-PGJ2 on the resolution of dextran sulfate sodium (DSS)-induced murine colitis that mimics human IBD. Pharmacologic inhibition of prostaglandin D synthase (PGDS) responsible for the synthesis of 15d-PGJ2 hampered resolution of inflammation in the colonic mucosa of mice treated with DSS. Notably, intraperitoneal injection of 15d-PGJ2 accelerated the resolution of experimentally induced colitis. 15d-PGJ2 treatment reduced the number of neutrophils and M1 macrophages, while it increased the proportion of M2 macrophages. Moreover, 15d-PGJ2 treated mice exhibited the significantly reduced proportion of macrophages expressing the pro-inflammatory cytokine, IL-6 with concomitant suppression of STAT3 phosphorylation in the colonic mucosa of mice administered 2.5% DSS in drinking water. Taken together, these findings clearly indicate that 15d-PGJ2, endogenously generated from arachidonic acid by cyclooxygenase-2 and PGDS activities in inflamed tissue, promotes resolution of intestinal colitis.

scholarly journals Identification and characterization of a novel Enterococcus bacteriophage with potential to ameliorate murine colitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Junko Nishio ◽  
Hideo Negishi ◽  
Mika Yasui-Kato ◽  
Shoji Miki ◽  
Kazuhiko Miyanaga ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Murine Colitis ◽  
Gut Homeostasis ◽  
Bowel Diseases ◽  
Mucin 2 ◽  
Inflammatory Bowel ◽  
Enterococcus Gallinarum ◽  
Identification And Characterization

AbstractIncrease of the enteric bacteriophages (phage), components of the enteric virome, has been associated with the development of inflammatory bowel diseases. However, little is known about how a given phage contributes to the regulation of intestinal inflammation. In this study, we isolated a new phage associated with Enterococcus gallinarum, named phiEG37k, the level of which was increased in C57BL/6 mice with colitis development. We found that, irrespective of the state of inflammation, over 95% of the E. gallinarum population in the mice contained phiEG37k prophage within their genome and the phiEG37k titers were proportional to that of E. gallinarum in the gut. To explore whether phiEG37k impacts intestinal homeostasis and/or inflammation, we generated mice colonized either with E. gallinarum with or without the prophage phiEG37k. We found that the mice colonized with the bacteria with phiEG37k produced more Mucin 2 (MUC2) that serves to protect the intestinal epithelium, as compared to those colonized with the phage-free bacteria. Consistently, the former mice were less sensitive to experimental colitis than the latter mice. These results suggest that the newly isolated phage has the potential to protect the host by strengthening mucosal integrity. Our study may have clinical implication in further understanding of how bacteriophages contribute to the gut homeostasis and pathogenesis.

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