Toll-like receptor 2 plays a critical role in maintaining mucosal integrity during Citrobacter rodentium-induced colitis

Abstract

SummaryInflammatory bowel diseases and infectious gastroenteritis likely occur when the integrity of intestinal barriers is disrupted allowing luminal bacterial products to cross into the intestinal mucosa, stimulating immune cells and triggering inflammation. While specific Toll-like receptors (TLR) are involved in the generation of inflammatory responses against enteric bacteria, their contributions to the maintenance of intestinal mucosal integrity are less clear. These studies investigated the role of TLR2 in a model of murine colitis induced by the bacterial pathogen Citrobacter rodentium. C. rodentium supernatants specifically activated TLR2 in vitro while infected TLR2-/-mice suffered a lethal colitis coincident with colonic mucosal ulcerations, bleeding and increased cell death but not increased pathogen burden. TLR2-/-mice suffered impaired epithelial barrier function mediated via zonula occludens (ZO)-1 in naïve mice and claudin-3 in infected mice, suggesting this could underlie their susceptibility. TLR2 deficiency was also associated with impaired production of IL-6 by bone marrow-derived macrophages and infected colons cultured ex vivo. As IL-6 has antiapoptotic and epithelial repair capabilities, its reduced expression could contribute to the impaired mucosal integrity. These studies report for the first time that TLR2 plays a critical role in maintaining intestinal mucosal integrity during infection by a bacterial pathogen.

Does TLR2 regulate intestinal inflammation?

“…Again this contrasts with previous findings of decreased numbers of Foxp3 1 Treg in TLR2 KO mice and that TLR2 may enhance Treg function [18]. Notably, TLR2 ligation has also been shown to induce retinoic acid production by DC, a property associated with gutderived DC, which drive differentiation of Foxp3 1 Treg [3].…”

Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier

“…Aside from these well-characterized functions, there is growing evidence from studies in knockout mice that a basal level of TLR activation is necessary for intestinal homeostasis (10,26,33). Our results identifying commensal bacterial stimulation of TLR2 in the gut epithelium as a regulator of epithelial integrity have important implications for understanding probiotic mechanisms and the control of intestinal homeostasis.…”

“…L. plantarum WCFS1 was grown on de Man, Rogosa and Sharpe (MRS) medium under anaerobic conditions, using standard laboratory procedures. Fifteen minutes before each experiment, 10 12 freshly prepared L. plantarum WCFS1 were resuspended in 2,400 ml saline and 10 g/l glucose at 37°C. Seven healthy nonsmoking subjects (28 Ϯ 6 yr), without a history of gastrointestinal complaints and free of any medication, participated in a double-blind randomized crossover study.…”

IL-6-Dependent Mucosal Protection Prevents Establishment of a Microbial Niche for Attaching/Effacing Lesion-Forming Enteric Bacterial Pathogens

“…Instead, the latter findings suggest that diffusible bacterial or host factors are responsible for most of the colonic IL-6 response. For example, bacterial products activate IL-6 expression in cultured macrophages through TLR2 and TLR4 (49), and TLR2 plays a role in activating IL-6 expression after C. rodentium infection (50).…”