Letter | Published:

Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes

Nature volume 514, pages 237241 (09 October 2014) | Download Citation

Abstract

The connection between an altered gut microbiota and metabolic disorders such as obesity, diabetes, and cardiovascular disease is well established1,2. Defects in preserving the integrity of the mucosal barriers can result in systemic endotoxaemia that contributes to chronic low-grade inflammation, which further promotes the development of metabolic syndrome3,4,5. Interleukin (IL)-22 exerts essential roles in eliciting antimicrobial immunity and maintaining mucosal barrier integrity within the intestine6,7. Here we investigate the connection between IL-22 and metabolic disorders. We find that the induction of IL-22 from innate lymphoid cells and CD4+ T cells is impaired in obese mice under various immune challenges, especially in the colon during infection with Citrobacter rodentium. While innate lymphoid cell populations are largely intact in obese mice, the upregulation of IL-23, a cytokine upstream of IL-22, is compromised during the infection. Consequently, these mice are susceptible to C. rodentium infection, and both exogenous IL-22 and IL-23 are able to restore the mucosal host defence. Importantly, we further unveil unexpected functions of IL-22 in regulating metabolism. Mice deficient in IL-22 receptor and fed with high-fat diet are prone to developing metabolic disorders. Strikingly, administration of exogenous IL-22 in genetically obese leptin-receptor-deficient (db/db) mice and mice fed with high-fat diet reverses many of the metabolic symptoms, including hyperglycaemia and insulin resistance. IL-22 shows diverse metabolic benefits, as it improves insulin sensitivity, preserves gut mucosal barrier and endocrine functions, decreases endotoxaemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. In summary, we identify the IL-22 pathway as a novel target for therapeutic intervention in metabolic diseases.

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Acknowledgements

We acknowledge S. Haller for her work in pathological analysis of colon samples. We thank F. Chu and J. Eastham-Anderson for performing the immunohistochemical staining and analysing pancreatic cell staining.

Author information

Author notes

    • Xiaoting Wang
    • , Naruhisa Ota
    •  & Ganesh Kolumam

    These authors contributed equally to this work.

Affiliations

  1. Department of Immunology, Genentech, South San Francisco, California 94080, USA

    • Xiaoting Wang
    • , Naruhisa Ota
    • , Paolo Manzanillo
    • , Celine Eidenschenk
    • , Juan Zhang
    • , Justin Lesch
    • , Wyne P. Lee
    •  & Wenjun Ouyang
  2. Department of Biomedical Imaging, Genentech, South San Francisco, California 94080, USA

    • Lance Kates
    • , Jose Zavala-Solorio
    • , Jed Ross
    • , Nicholas van Bruggen
    •  & Ganesh Kolumam
  3. Department of Pathology, Genentech, South San Francisco, California 94080, USA

    • Lauri Diehl

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Contributions

W.O. and G.K. devised the project. X.W. and N.O. designed and performed most of the experiments and analyses. P.M. performed western blot and contributed to lipid metabolism studies. G.K., L.K., J.Z.-S., and J.R. contributed to metabolic studies. C.E. and J.L. contributed to flagellin stimulation studies. J.Z. and W.P.L. contributed to ovalbumin/complete Freund’s adjuvant stimulation studies. L.D. did all histology analyses. W.O., X.W., and N.O. prepared the manuscript. N.v.B., P.M., C.E., and G.K. helped to edit the manuscript.

Competing interests

All authors are employees of Genentech Inc.

Corresponding authors

Correspondence to Ganesh Kolumam or Wenjun Ouyang.

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DOI

https://doi.org/10.1038/nature13564

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