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Original article
Interleukin-1β (IL-1β) promotes susceptibility of Toll-like receptor 5 (TLR5) deficient mice to colitis
  1. Frederic A Carvalho1,
  2. Ilke Nalbantoglu2,
  3. Sophie Ortega-Fernandez1,
  4. Jesse D Aitken1,
  5. Yueju Su1,
  6. Omry Koren3,
  7. William A Walters4,
  8. Rob Knight5,
  9. Ruth E Ley3,
  10. Matam Vijay-Kumar1,
  11. Andrew T Gewirtz1
  1. 1Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA
  2. 2Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA
  3. 3Department of Microbiology, Cornell University, Ithaca, New York, USA
  4. 4Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado, USA
  5. 5Howard Hughes Medical Institute and Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado, USA
  1. Correspondence to Andrew T Gewirtz, Department of Pathology, Emory University School of Medicine, WBRB, Room 105H, 615 Michael Street, Atlanta, GA 30322, USA; agewirt{at}emory.edu

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.

Conclusion 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.

  • TLR5
  • IL-10 receptor neutralisation
  • IL-1β
  • gut microbial diversity
  • 16S rRNA gene pyrosequencing
  • inflammatory bowel disease
  • mucosal immunology

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Footnotes

  • Funding This work was supported by NIH grants DK061417 and DK083890 to ATG. FAC and MVK 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), and support to OK (HMP DACC), REL (The Hartwell Foundation and the Arnold and Mabel Beckman Foundation) and RK (NIH HG004872, Crohns and Colitis Foundation of America, and the Howard Hughes Medical Institute).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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