Pathogenic and protective roles of MyD88 in leukocytes and epithelial cells in mouse models of inflammatory bowel disease

Gastroenterology. 2010 Aug;139(2):519-29, 529.e1-2. doi: 10.1053/j.gastro.2010.04.045. Epub 2010 Apr 28.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Adoptive Transfer
  • Animals
  • Bone Marrow Transplantation
  • Cecum / immunology
  • Cecum / microbiology
  • Colitis / immunology*
  • Colitis / microbiology
  • Colitis / pathology
  • Colitis / prevention & control
  • Colon / immunology*
  • Colon / microbiology
  • Colon / pathology
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Epithelial Cells / immunology*
  • Epithelial Cells / microbiology
  • Epithelial Cells / pathology
  • Helicobacter hepaticus / pathogenicity
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Immunity, Innate
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / microbiology
  • Intestinal Mucosa / pathology
  • Leukocytes / immunology*
  • Leukocytes / microbiology
  • Leukocytes / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / deficiency
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / immunology*
  • Signal Transduction
  • Toll-Like Receptors / immunology*
  • Transplantation Chimera

Substances

  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Rag2 protein, mouse
  • Toll-Like Receptors
  • RAG-1 protein