MyD 88 signalling in colonic mononuclear phagocytes drives colitis in IL-10-deficient mice

Commensal bacterial sensing by Toll-like receptors (TLRs) is critical for maintaining intestinal homeostasis, but can lead to colitis in the absence of IL-10. While TLRs are expressed in multiple cell types in the colon, the cell type(s) responsible for the development of colitis currently unknown. Here, we generated mice that are selectively deficient in MyD88 in various cellular compartments in an IL-10−/− setting. While epithelial expression of MyD88 was dispensable, MyD88 expression in the mononuclear phagocyte (MNP) compartment was required for colitis development. Specifically, phenotypically distinct populations of colonic MNPs expressed high levels IL-1β, IL-23 and IL-6 and promoted Th17 responses in the absence of IL-10. Thus, gut bacterial sensing through MyD88 in MNPs drives inflammatory bowel disease (IBD) when unopposed by IL-10. Increasing evidence supports the notion that (IBD) results from a dysregulated interaction between the host immune system and its commensal microbiota1. Commensal bacteria are most abundant in the colon and they normally co-exist with the host in a mutually beneficial relationship. At the same time, the mammalian host must maintain the ability to recognize pathogenic microbes in the colon and respond appropriately to contain and eliminate them. While the exact mechanism by which commensal bacteria and pathogenic bacteria are distinguished is unclear, recent evidence indicates that multiple mechanisms exist to limit inflammatory immune responses against commensal microbes. One such mechanism involves secretion of IL-10 in the intestinal mucosa. In the absence of IL-10, mice develop Correspondence should be addressed to R.M. (ruslan.medzhitov@yale.edu). Author contributions N.H. conducted the experiments; D.S. generated the MyD88FL mice and designed some experiments; N.H. and S.N. designed the experiments; Z.W. performed histological scoring; N.G and R.F. provided the endoscopic system and performed endoscopic analysis; B.R. provided CD1c-Cre mice; Z.S. and J.F. tested helicobacter PCR in mice colony; N.H., A.I. and R.M. prepared the manuscript; R.M. directed the research. Competing financial interests The authors declare no competing financial interests. NIH Public Access Author Manuscript Nat Commun. Author manuscript; available in PMC 2012 December 13. Published in final edited form as: Nat Commun. 2012 ; 3: 1120. doi:10.1038/ncomms2113.