Deletion of TLR5 results in spontaneous colitis in mice

• Type of Material: Article
• Authors: Matam Vijay-Kumar, Emory University; Catherine J. Sanders, Emory University; Rebekah T. Taylor, Emory University; Amrita Kumar, Emory University; Jesse D. Aitken, Emory University; Shanthi V. Sitaraman, Emory University; Andrew S Neish, Emory University; Satoshi Uematsu, Research Institute for Microbial Diseases; Shizuo Akira, Research Institute for Microbial Diseases; Ifor Williams, Emory University; Andrew T Gewirtz, Emory University
• Language: English
• Date: 2007-12-03
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2007, American Society for Clinical Investigation
• Final Published Version (URL): http://www.jci.org/articles/view/33084
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 117
• Issue: 12
• Start Page: 3909
• End Page: 3921
• Grant/Funding Information: M. Vijay-Kumar is a recipient of a research fellowship from the Crohn’s and Colitis Foundation of America.; We also acknowledge NIH Digestive Disease Research and Development Center grants to Emory University (DK064399).; This work was supported by grants from the Broad Medical Research Foundation, the Crohn’s and Colitis Foundation of America, and the NIH (DK061417) to A.T. Gewirtz.
• Research Categories: Health Sciences, General; Health Sciences, Pathology

Abstract

Activation of TLRs by bacterial products results in rapid activation of genes encoding products designed to protect the host from perturbing microbes. In the intestine, which is colonized by a large and diverse population of commensal bacteria, TLR signaling may not function in a simple on/off mode. Here, we show that the flagellin receptor TLR5 has an essential and nonredundant role in protecting the gut from enteric microbes. Mice lacking TLR5 (TLR5KO mice) developed spontaneous colitis, as assessed by well-defined clinical, serologic, and histopathologic indicators of this disorder. Compared with WT littermates, TLR5KO mice that had not yet developed robust colitis exhibited decreased intestinal expression of TLR5-regulated host defense genes despite having an increased bacterial burden in the colon. In contrast, such TLR5KO mice displayed markedly increased colonic expression of hematopoietic-derived proinflammatory cytokines, suggesting that elevated levels of bacterial products may result in activation of other TLRs that drive colitis in TLR5KO mice. In accordance, deletion of TLR4 rescued the colitis of TLR5KO mice in that mice lacking both TLR4 and TLR5 also had elevated bacterial loads in the colon but lacked immunological, histopathological, and clinical evidence of colitis. That an engineered innate immune deficiency ultimately results in spontaneous intestinal inflammation supports the notion that an innate immune deficiency might underlie some instances of inflammatory bowel disease.