HOME
Return to Table of Contents
TOLL SIGNALING IS CRITICAL FOR MAINTAINING INTESTINAL HOMEOSTASIS DURING CITROBACTER RODENTIUM INDUCED COLITIS
DL Gibson, BA Vallance
Division of Gastroenterology, BC Children’s Hospital, UBC, Vancouver, British Columbia
The role of innate responses during gastrointestinal (GI) bacterial infections is somewhat unclear. This is in part because the GI tract is tolerant to commensal bacterial products yet mounts effective immune responses to enteric pathogens. The current study investigated the role of the Toll-interleukin 1 innate adaptor protein, Myeloid Differentiation Factor (MyD)88, and an innate receptor, Toll-like receptor (TLR)2, in a model of murine colitis induced by the enteric bacterial pathogen Citrobacter rodentium. MyD88–/– and TLR2–/– mice suffered a lethal colitis coincident with colonic mucosal ulcerations and bleeding. MyD88–/– mice but not TLR2–/– mice developed an overwhelming bacterial burden and impaired immune responses in colonic tissues which included delayed inflammatory cell recruitment, reduced iNOS expression and abrogated production of TNF-alpha. Both MyD88–/– and TLR2–/– mice suffered impaired epithelial barrier function under naïve and infected conditions, suggesting the inability to maintain mucosal integrity could underlie their susceptibility. In the absence of TLR2, barrier dysfunction was mediated via zonula occludens-1 in naïve mice and claudin-3 in infected mice. Both KO mice were impaired in their abilities to produce IL-6 from bone marrow derived macrophages and colons cultured ex vivo. Since IL-6 has anti-apoptotic and epithelial repair capabilities, its reduced expression could contribute to the impaired mucosal integrity. Immunostaining for Ki67 and BrDU revealed that MyD88 signaling mediated epithelial hyper-proliferation in response to C. rodentium infection. Thus, MyD88–/– mice could not promote epithelial cell turnover and repair leading to deep bacterial invasion of colonic crypts, intestinal barrier dysfunction and ultimately to widespread mucosal ulcerations. In conclusion, MyD88 signaling within the GI tract plays a critical role in mediating host defense against an enteric bacterial pathogen, by controlling bacterial numbers and promoting intestinal epithelial homeostasis while TLR2-dependent mechanisms maintain intestinal mucosal integrity.