Pathogenic and protective roles of MyD88 in leukocytes and epithelial cells in mouse models of inflammatory bowel disease.
OBJECTIVE
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.
Asquith
Mark J
MJ
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
Boulard
Olivier
O
Powrie
Fiona
F
Maloy
Kevin J
KJ
D056704:Adaptive Immunity; D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation; D002432:Cecum / Q000276:immunology / Q000382:microbiology; D003092:Colitis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D003106:Colon / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D044923:Helicobacter hepaticus / Q000472:pathogenicity; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D007962:Leukocytes / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology*; D018183:Transplantation Chimera
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C499308:Rag2 protein, mouse; D051193:Toll-Like Receptors; C064658:RAG-1 protein