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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.

Original publication

DOI

10.1053/j.gastro.2010.04.045

Type

Journal article

Journal

Gastroenterology

Publication Date

08/2010

Volume

139

Pages

519 - 529.e2

Keywords

Adaptive Immunity, Adoptive Transfer, Animals, Bone Marrow Transplantation, Cecum, Colitis, Colon, DNA-Binding Proteins, Disease Models, Animal, Epithelial Cells, Helicobacter hepaticus, Homeodomain Proteins, Immunity, Innate, Intestinal Mucosa, Leukocytes, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88, Signal Transduction, Toll-Like Receptors, Transplantation Chimera