Cytosolic flagellin receptor NLRC4 protects mice against mucosal and systemic challenges

• Type of Material: Article
• Authors: Frederic A. Carvalho, Georgia State University; Ilke Nalbantoglu, Washington University; Jesse D. Aitken, Georgia State University; Robin Uchiyama, Georgia State University; Yueju Su, Georgia State University; Gregory H. Doho, Emory University; Matam Vijay-Kumar, Georgia State University; Andrew T Gewirtz, Emory University
• Language: English
• Date: 2012-05-01
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Society for Mucosal Immunology.
• Final Published Version (URL): http://dx.doi.org/10.1038/mi.2012.8
• Title of Journal or Parent Work: Mucosal Immunology
• ISSN: 1933-0219
• Volume: 5
• Issue: 3
• Start Page: 288
• End Page: 298
• Grant/Funding Information: This work was supported by NIH grants DK061417 and DK083890 to A.T. Gewirtz.; F.A. Carvalho and M. Vijay-Kumar are recipients of, respectively, Research Fellowship and Career Development awards from the Crohn’s and Colitis Foundation of America.; We also acknowledge NIH Digestive Disease Research and Development Center (DDRDC) grants to Emory University (DK064399).
• Keywords: BACTERIAL FLAGELLIN; IMMUNE-RESPONSE; INFLAMMASOME; TLR5; TOLL-LIKE RECEPTOR-5; Science & Technology; COLITIS; Immunology; SALMONELLA-TYPHIMURIUM; GENE-EXPRESSION; ACTIVATION; Life Sciences & Biomedicine; DISEASE
• Research Categories: Health Sciences, Immunology; Health Sciences, Pathology

Abstract

Bacterial flagellin is a dominant innate immune activator of the intestine. Therefore, we examined the role of the intracellular flagellin receptor, NLRC4, in protecting the gut and/or driving inflammation. In accordance with NLRC4 acting through transcription-independent pathways, loss of NLRC4 did not reduce the rapid robust changes in intestinal gene expression induced by flagellin administration. Loss of NLRC4 did not alter basal intestinal homeostasis nor predispose mice to development of colitis upon administration of an anti-interleukin (IL)-10R monoclonal antibody. However, epithelial injury induced by dextran sulfate sodium in mice lacking NLRC4 resulted in a more severe disease, indicating a role for NLRC4 in protecting the gut. Moreover, loss of NLRC4 resulted in increased mortality in response to flagellate, but not aflagellate Salmonella infection. Thus, despite not being involved in rapid intestinal gene remodeling upon detection of flagellin, NLRC4-mediated inflammasome activation results in production of IL-1β and IL-18, two cytokines that protect mice from mucosal and systemic challenges.