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Interleukin-17–producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity

Nature Medicine volume 20, pages 54–61 (2014)Cite this article

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Abstract

Obesity is associated with the development of asthma, which is often difficult to control. To understand the immunological pathways that lead to obesity-associated asthma, we fed mice a high-fat diet for 12 weeks, which resulted in obesity and the development of airway hyperreactivity (AHR), a cardinal feature of asthma. This AHR was independent of adaptive immunity, as it occurred in obese Rag1−/− mice, which lack B and T cells, and was dependent on interleukin-17A (IL-17A) and the NLRP3 inflammasome, as it did not develop in obese Il17a−/− or Nlrp3−/− mice. AHR was also associated with the expansion of CCR6+ type 3 innate lymphoid cells (ILCs) producing IL-17A (ILC3 cells) in the lung, which could by themselves mediate AHR when adoptively transferred into Rag2−/−; Il2rg−/− mice treated with recombinant IL-1β. Macrophage-derived IL-1β production was induced by HFD and expanded the number of lung ILC3 cells. Blockade of IL-1β with an IL-1 receptor antagonist abolished obesity-induced AHR and reduced the number of ILC3 cells. As we found ILC3-like cells in the bronchoalveolar lavage fluid of individuals with asthma, we suggest that obesity-associated asthma is facilitated by inflammation mediated by NLRP3, IL-1β and ILC3 cells.

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Figure 1: HFD and obesity induces AHR in WT mice.
Figure 2: HFD-induced AHR requires IL-17A.
Figure 3: IL-1β production and M1 macrophages are increased in the lungs of obese mice.
Figure 4: NLRP3 is induced in HFD-fed mice and is required for AHR.
Figure 5: IL-17–producing ILCs are required for the development of AHR.
Figure 6: Treatment of obese mice with an IL-1R antagonist prevents AHR.

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Acknowledgements

We thank the National Institutes of Health Tetramer Facility, Emory University, Atlanta, Georgia, for providing CD1d tetramers. This work was supported by grants RO1AI068085, RO1HL62348 and ES013307 from the US National Institutes of Health and with funds from The D. and D. Bunning Food Allergy Project.

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  1. Present addresses: Korean Research Institute of Bioscience and Biotechnology, Daejeon, Korea (H.J.L.) and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (Y.-J.C.).

Authors and Affiliations

  1. Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Hye Young Kim, Hyun Jun Lee, Ya-Jen Chang, Muriel Pichavant, Rosemarie H DeKruyff & Dale T Umetsu

  2. Harvard School of Public Health, Boston, Massachusetts, USA

    Stephanie A Shore

  3. Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts, Worcester, Massachusetts, USA

    Katherine A Fitzgerald

  4. Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan

    Yoichiro Iwakura

  5. Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Elliot Israel

  6. Respiratory Department, Connolly Hospital Blanchardstown, Dublin, Ireland

    Kenneth Bolger & John Faul

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Contributions

H.Y.K. designed the study, did the experiments, analyzed the data and wrote the manuscript; H.J.L. did SFB experiments and analyzed the data; Y.-J.C. helped with the experiments involving human cells; M.P. did experiments; S.A.S. analyzed the data and edited the manuscript; K.A.F. and Y.I. provided Nlrp3−/− and Il17a−/− mice; E.I., K.B. and J.F. provided human BAL fluid samples and information; R.H.D. provided reagent support and edited the manuscript; and D.T.U. designed the study and wrote the manuscript.

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Correspondence to Dale T Umetsu.

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Kim, H., Lee, H., Chang, YJ. et al. Interleukin-17–producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat Med 20, 54–61 (2014). https://doi.org/10.1038/nm.3423

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