Pathogenic and Protective Roles of MyD88 in Leukocytes and Epithelial Cells in Mouse Models of Inflammatory Bowel Disease

Background & Aims

Toll-like receptors (TLR) are innate immune receptors involved in recognition of the intestinal microflora; they are expressed by numerous cell types in the intestine, including epithelial cells, myeloid cells, and lymphocytes. Little is known about the relative contributions of TLR signaling in distinct cellular compartments to intestinal homeostasis. We aimed to define the roles of TLR signals in distinct cell types in the induction and regulation of chronic intestinal inflammation.

Methods

We assessed the roles of the shared TLR signaling adaptor protein, MyD88, in several complementary mouse models of inflammatory bowel disease, mediated by either innate or adaptive immune activation. MyD88-deficient mice and bone marrow chimeras were used to disrupt TLR signals selectively in distinct cellular compartments in the intestine.

Results

MyD88-dependent activation of myeloid cells was required for the development of chronic intestinal inflammation. By contrast, although epithelial cell MyD88 signals were required for host survival, they were insufficient to induce intestinal inflammation in the absence of an MyD88-competent myeloid compartment. MyD88 expression by T cells was not required for their pathogenic and regulatory functions in the intestine.

Conclusions

Cellular compartmentalization of MyD88 signals in the intestine allow the maintenance of host defense and prevent deleterious inflammatory responses.

Keywords: Helicobacter Hepaticus, Colitis, PRR, Treg

Abbreviations used in this paper: AMP, antimicrobial peptide, IBD, inflammatory bowel disease, IEC, intestinal epithelial cells, IFN, interferon, IL, interleukin, IP, intraperitoneally, mRNA, messenger RNA, PBS, phosphate-buffered saline, SPF, specific pathogen free, TLR, Toll-like receptor, TNF, tumor necrosis factor, Treg, regulatory T cells