Abstract

Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer1. This association could be explained by the hypothesis that the same factors and pathways important for wound healing also promote tumorigenesis. A sensor of tissue damage should induce these factors to promote tissue repair and regulate their action to prevent development of cancer. Interleukin 22 (IL-22), a cytokine of the IL-10 superfamily, has an important role in colonic epithelial cell repair, and its levels are increased in the blood and intestine of inflammatory bowel disease patients2,3. This cytokine can be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP, also known as IL22RA2); however, the significance of endogenous IL-22BP in vivo and the pathways that regulate this receptor are unknown4,5. Here we describe that IL-22BP has a crucial role in controlling tumorigenesis and epithelial cell proliferation in the colon. IL-22BP is highly expressed by dendritic cells in the colon in steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes led to an IL-18-dependent downregulation of IL-22BP, thereby increasing the ratio of IL-22/IL-22BP. IL-22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumour development if uncontrolled during the recovery phase. Thus, the IL-22–IL-22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.

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Acknowledgements

The authors would like to thank F. Manzo for expert administrative assistance, E. Eynon and J. Alderman for managing the mouse program. We also thank T. Taylor and G. Tokmoulina for expert help with the FACS sorting. R.A.F. is an Investigator of the Howard Hughes Medical Institute. S.H. was supported by a post-doctoral fellowship from the Crohn’s and Colitis Foundation of America, the ‘Stiftung experimentelle Biomedizin’ and the Ernst Jung Foundation. N.G. was supported by an EMBO post-doctoral fellowship. L.A.Z. was supported by a post-doctoral fellowship from the American Cancer Society. A.J.M., D.M.V. and G.D.Y. were employees of Regeneron Pharmaceuticals at the time this work was performed. W.O. is an employee of Genentech Inc. This work was supported by R01DK077905, DK-P30-34989 and U19-AI082713 (to C.A. and R.A.F.) and by the DFG, SFB841 (to S.H.).

Author information

Author notes

    • Samuel Huber
    •  & Nicola Gagliani

    These authors contributed equally to this work.

Affiliations

  1. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Samuel Huber
    • , Nicola Gagliani
    • , Lauren A. Zenewicz
    • , Lidia Bosurgi
    • , Bo Hu
    • , William O’Connor
    •  & Richard A. Flavell
  2. I. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany

    • Samuel Huber
    •  & Francis J. Huber
  3. Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut 06520, USA

    • Matija Hedl
    •  & Clara Abraham
  4. Departments of Medicine and Genetics, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Wei Zhang
    •  & Judy H. Cho
  5. Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591, USA

    • Andrew J. Murphy
    • , David M. Valenzuela
    •  & George D. Yancopoulos
  6. Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Carmen J. Booth
  7. Department of immunology, Genentech, Inc., South San Francisco, California 94080, USA

    • Wenjun Ouyang
  8. Howard Hughes Medical Institute, New Haven, Connecticut 06520, USA

    • Richard A. Flavell

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Contributions

R.A.F., S.H. and N.G. designed the experiments, analysed the data and wrote the manuscript. L.A.Z. performed colitis-associated colon cancer experiments with Il22−/− single-KO mice, and provided Il22−/− mice. F.J.H. assisted during the mouse endoscopy. L.B. performed immuno histochemistry. B.H. provided mice for colitis-associated cancer experiment. W.O.C. made key suggestions for experiments and edited the manuscript. A.J.M., D.M.V. and G.D.Y. generated Il22bp−/− mice and are employees of Regeneron Pharmaceuticals Inc. C.J.B. performed the histopathological analyses. W.O. provided IL-22 antibody and is an employee of Genentech. W.Z., J.H.C, C.A. and M.H. did the experiments using human material. S.H. and N.G. performed all other experiments.

Competing interests

A.J.M, D.M.V. and G.D.Y. are employees of Regeneron Pharmaceuticals. W.O. is an employee of Genentech Inc.

Corresponding author

Correspondence to Samuel Huber.

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DOI

https://doi.org/10.1038/nature11535

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