B Cell-Intrinsic MyD88 Signaling Prevents the Lethal Dissemination of Commensal Bacteria during Colonic Damage

Department of Immunology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Immunity (Impact Factor: 21.56). 02/2012; 36(2):228-38. DOI: 10.1016/j.immuni.2011.11.019
Source: PubMed


The Toll-like receptor adaptor protein MyD88 is essential for the regulation of intestinal homeostasis in mammals. In this study, we determined that Myd88-deficient mice are susceptible to colonic damage that is induced by dextran sulfate sodium (DSS) administration resulting from uncontrolled dissemination of intestinal commensal bacteria. The DSS-induced mortality of Myd88-deficient mice was completely prevented by antibiotic treatment to deplete commensal bacteria. By using cell type-specific Myd88-deficient mice, we established that B cell-intrinsic MyD88 signaling plays a central role in the resistance to DSS-induced colonic damage via the production of IgM and complement-mediated control of intestinal bacteria. Our results indicate that the lack of intact MyD88 signaling in B cells, coupled with impaired epithelial integrity, enables commensal bacteria to function as highly pathogenic organisms, causing rapid host death.

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    • "In addition, several barriers including the mucus layer and antimicrobial peptides limit the contact between microbes and the host immune system and contribute to gut homeostasis (Kamada and Nú n ˜ ez, 2014). A role for the microbiota in eliciting intestinal inflammation is supported by findings that chemically-induced and spontaneous colitis are reduced or abolished in antibiotic-treated mice and germ-free mice (Garrett et al., 2007; Hudcovic et al., 2001; Kirkland et al., 2012; Kitajima et al., 2001; Vijay-Kumar et al., 2007). In mouse models, certain members of the microbiota have been linked to inflammatory responses and intestinal pathology. "
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    ABSTRACT: The microbiota stimulates inflammation, but the signaling pathways and the members of the microbiota involved remain poorly understood. We found that the microbiota induces interleukin-1β (IL-1β) release upon intestinal injury and that this is mediated via the NLRP3 inflammasome. Enterobacteriaceae and in particular the pathobiont Proteus mirabilis, induced robust IL-1β release that was comparable to that induced by the pathogen Salmonella. Upon epithelial injury, production of IL-1β in the intestine was largely mediated by intestinal Ly6C(high) monocytes, required chemokine receptor CCR2 and was abolished by deletion of IL-1β in CCR2(+) blood monocytes. Furthermore, colonization with P. mirabilis promoted intestinal inflammation upon intestinal injury via the production of hemolysin, which required NLRP3 and IL-1 receptor signaling in vivo. Thus, upon intestinal injury, selective members of the microbiota stimulate newly recruited monocytes to induce NLRP3-dependent IL-1β release, which promotes inflammation in the intestine. Copyright © 2015 Elsevier Inc. All rights reserved.
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    • "Several studies have also highlighted the importance of TLR-MyD88 signaling among lymphocytes. In B cell–specific MyD88-deficient mice, bacteria disseminate to systemic sites, such as liver or lung, after DSS-induced damage of the colon, but not in epithelial cell–specific or dendritic cell–specific MyD88-deficient mice (22). Further, it has recently been appreciated that T cell subsets express functional TLRs (23). "
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    ABSTRACT: The intestinal mucosa plays a critical role in the host's interactions with innocuous commensal microbiota and invading pathogenic microorganisms. Intestinal epithelial cells (IECs) and gut associated immune cells recognize the bacterial components via pattern-recognition receptors (PRRs) and are responsible for maintaining tolerance to the large communities of resident luminal bacteria while being also able to mount inflammatory responses against pathogens. Toll-like receptors (TLRs) are a major class of PRRs that are present on IECs and immune cells which are involved in the induction of both tolerance and inflammation. A growing body of experimental and clinical evidence supports the therapeutic and preventive application of probiotics for several gastrointestinal inflammatory disorders in which TLRs exert a significant role. This review aims to summarize the current knowledge of the beneficial effects of probiotic microorganisms with the capacity to modulate the immune system (immunobiotics) in the regulation of intestinal inflammation in pigs, which are very important as both livestock and human model. Especially we discuss the role of TLRs, their signaling pathways, and their negative regulators in both the inflammatory intestinal injury and the beneficial effects of immunobiotics in general, and Lactobacillus jensenii TL2937 in particular. This review article emphasizes the cellular and molecular interactions of immunobiotics with IECs and immune cells through TLRs and their application for improving animal and human health.
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    • "Microbial antigens presented to B cells induce a commensal-specific IgA response that aids to prevent the commensals from straying beyond the gut mucosa [9]. Interestingly, mice deficient in the TLR-adapter molecule MyD88 on B cells lack commensal-specific immunoglobulin-response with insufficient bacterial killing that leads to lethal dissemination of commensal bacteria during colonic damage [10]. In cirrhotic patients, reductions in memory B cells and hypo-responsiveness to TLR9-stimu- lation has been reported [11]. "

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