title: Interleukin-1β (IL-1β) promotes susceptibility of Toll-like receptor 5 (TLR5) deficient mice to colitis.
abstract: BACKGROUND
  The extent to which numerous strains of genetically engineered mice, including mice lacking Toll-like receptor 5 (T5KO), display colitis is environment dependent. Gut microbiota underlie much of the variation in phenotype. Accordingly, embryonic rederivation of T5KO mice ameliorated their spontaneous colitis despite only partially correcting elevated proinflammatory gene expression. It was postulated that endogenous anti-inflammatory pathways mediated the absence of overt inflammation in these mice when their gut microbiota were reset. Consequently, it was hypothesised that neutralisation of the anti-inflammatory cytokine interleukin 10 (IL-10) might induce uniform colitis in T5KO mice, and thus provide a practical means to study mechanisms underlying their inflammation.
  
  
  METHODS
  Two distinct strains of non-colitic T5KO mice, as well as mice lacking MyD88, Toll-like receptor 4 (TLR4), IL-1 receptor (IL-1R) and various double knockouts (DKOs) were treated weekly for 4  weeks with 1 mg/mouse of IL-10 receptor neutralising antibody (IL-10R mAb) and colitis assayed 1 week later. The composition of the caecal microbiota was determined by 454 pyrosequencing of 16S rRNA genes.
  
  
  RESULTS
  Anti-IL-10R mAb treatment led to severe uniform intestinal inflammation in both strains of T5KO mice. Such neutralisation of IL-10 signalling did not cause colitis in wild-type littermates nor mice lacking TLR4, MyD88 or IL-1R. The susceptibility of T5KO mice to this colitis model was not rescued by absence of TLR4 in that T4/T5 DKO mice displayed severe colitis in response to anti-IL-10R mAb treatment. IL-1β signalling was crucial for this colitis model in that IL-1R/T5 DKOs were completely protected from colitis in response to IL-10R mAb treatment. Lastly, it was observed that blockade of IL-10R function was associated with changes in the composition of gut microbiota, which were observed in mice that were susceptible and resistant to IL-10R mAb-induced colitis.
  
  
  CONCLUSIONS
  Regardless of whether they harbour a colitogenic microbiota, loss of TLR5 predisposes mice to colitis triggered by immune dysregulation via an IL-1β-dependent pathway.
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Frederic A
authors.initials: FA
authors.lastname: Carvalho
authors.forename: Ilke
authors.initials: I
authors.lastname: Nalbantoglu
authors.forename: Sophie
authors.initials: S
authors.lastname: Ortega-Fernandez
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Aitken
authors.forename: Yueju
authors.initials: Y
authors.lastname: Su
authors.forename: Omry
authors.initials: O
authors.lastname: Koren
authors.forename: William A
authors.initials: WA
authors.lastname: Walters
authors.forename: Rob
authors.initials: R
authors.lastname: Knight
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Ley
authors.forename: Matam
authors.initials: M
authors.lastname: Vijay-Kumar
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Gewirtz
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002432:Cecum / Q000382:microbiology; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D020869:Gene Expression Profiling / Q000379:methods; D053583:Interleukin-1beta / Q000502:physiology*; D008297:Male; D054892:Metagenome / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D053701:Receptors, Interleukin-10 / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000172:deficiency* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053701:Receptors, Interleukin-10; D051198:Toll-Like Receptor 5