title: Deletion of TLR5 results in spontaneous colitis in mice.
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.
authors.affiliation: Department of Pathology, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Matam
authors.initials: M
authors.lastname: Vijay-Kumar
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Sanders
authors.forename: Rebekah T
authors.initials: RT
authors.lastname: Taylor
authors.forename: Amrita
authors.initials: A
authors.lastname: Kumar
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Aitken
authors.forename: Shanthi V
authors.initials: SV
authors.lastname: Sitaraman
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Neish
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Ifor R
authors.initials: IR
authors.lastname: Williams
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Gewirtz
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology; D003092:Colitis / Q000235:genetics* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005408:Flagellin / Q000276:immunology; D017353:Gene Deletion; D007113:Immunity, Innate / Q000235:genetics*; D018836:Inflammation Mediators / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000235:genetics* / Q000276:immunology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D005408:Flagellin