Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Flegal, K.M., Carroll, M.D., Kit, B.K. & Ogden, C.L. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. J. Am. Med. Assoc. 307, 491–497 (2012).

    Article  Google Scholar 

  2. Osborn, O. & Olefsky, J.M. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18, 363–374 (2012).

    PubMed  CAS  Article  Google Scholar 

  3. Wenzel, S.E. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat. Med. 18, 716–725 (2012).

    PubMed  CAS  Article  Google Scholar 

  4. Holguin, F. et al. Obesity and asthma: an association modified by age of asthma onset. J. Allergy Clin. Immunol. 127, 1486–1493.e2 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  5. Camargo, C.A. Jr., Weiss, S.T., Zhang, S., Willett, W.C. & Speizer, F.E. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch. Intern. Med. 159, 2582–2588 (1999).

    PubMed  Article  Google Scholar 

  6. Dixon, A.E. et al. Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. J. Allergy Clin. Immunol. 128, 508–515.e1–2 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  7. Sutherland, E.R., Lehman, E.B., Teodorescu, M. & Wechsler, M.E. Body mass index and phenotype in subjects with mild-to-moderate persistent asthma. J. Allergy Clin. Immunol. 123, 1328–1334.e1 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  8. Shore, S.A. Obesity, airway hyperresponsiveness, and inflammation. J. Appl. Physiol. 108, 735–743 (2010).

    PubMed  Article  Google Scholar 

  9. Farah, C.S. & Salome, C.M. Asthma and obesity: a known association but unknown mechanism. Respirology 17, 412–421 (2012).

    PubMed  Article  Google Scholar 

  10. Kanneganti, T.D. & Dixit, V.D. Immunological complications of obesity. Nat. Immunol. 13, 707–712 (2012).

    PubMed  CAS  Article  Google Scholar 

  11. Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  12. Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).

    PubMed  CAS  Article  Google Scholar 

  13. Olefsky, J.M. & Glass, C.K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).

    PubMed  CAS  Article  Google Scholar 

  14. Scott, H.A., Gibson, P.G., Garg, M.L. & Wood, L.G. Airway inflammation is augmented by obesity and fatty acids in asthma. Eur. Respir. J. 38, 594–602 (2011).

    PubMed  CAS  Article  Google Scholar 

  15. Chen, Y., Dales, R. & Jiang, Y. The association between obesity and asthma is stronger in nonallergic than allergic adults. Chest 130, 890–895 (2006).

    PubMed  Article  Google Scholar 

  16. Moore, W.C. et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am. J. Respir. Crit. Care Med. 181, 315–323 (2010).

    PubMed  Article  Google Scholar 

  17. Lu, F.L. et al. Increased pulmonary responses to acute ozone exposure in obese db/db mice. Am. J. Physiol. Lung Cell Mol. Physiol. 290, L856–L865 (2006).

    PubMed  CAS  Article  Google Scholar 

  18. Arteaga-Solis, E. et al. Inhibition of leptin regulation of parasympathetic signaling as a cause of extreme body weight-associated asthma. Cell Metab. 17, 35–48 (2013).

    PubMed  CAS  Article  Google Scholar 

  19. Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  20. Geremia, A. et al. IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease. J. Exp. Med. 208, 1127–1133 (2011).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  21. Coccia, M. et al. IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ TH17 cells. J. Exp. Med. 209, 1595–1609 (2012).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  22. Klose, C.S. et al. A T-bet gradient controls the fate and function of CCR6-RORγt+ innate lymphoid cells. Nature 494, 261–265 (2013).

    PubMed  CAS  Article  Google Scholar 

  23. Sun, Z. et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000).

    PubMed  CAS  Article  Google Scholar 

  24. Sawa, S. et al. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol. 12, 320–326 (2011).

    PubMed  CAS  Article  Google Scholar 

  25. Cupedo, T. et al. Human fetal lymphoid tissue-inducer cells are interleukin 17–producing precursors to RORC+ CD127+ natural killer–like cells. Nat. Immunol. 10, 66–74 (2009).

    PubMed  CAS  Article  Google Scholar 

  26. Sanos, S.L. et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22–producing NKp46+ cells. Nat. Immunol. 10, 83–91 (2009).

    PubMed  CAS  Article  Google Scholar 

  27. Luci, C. et al. Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin. Nat. Immunol. 10, 75–82 (2009).

    PubMed  CAS  Article  Google Scholar 

  28. Chang, Y.-J. et al. Innate lymphoid cells mediate influenza-induced airway hyperreactivity independent of adaptive immunity. Nat. Immunol. 12, 631–638 (2011).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  29. Halim, T.Y., Krauss, R.H., Sun, A.C. & Takei, F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36, 451–463 (2012).

    PubMed  CAS  Article  Google Scholar 

  30. Klein Wolterink, R.G. et al. Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur. J. Immunol. 42, 1106–1116 (2012).

    PubMed  Article  CAS  Google Scholar 

  31. Spits, H. et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

    PubMed  CAS  Article  Google Scholar 

  32. Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  33. Ivanov, I.I. et al. Induction of intestinal TH17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  34. Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).

    PubMed  CAS  Article  Google Scholar 

  35. Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17–producing T cells. Immunity 24, 179–189 (2006).

    PubMed  CAS  Article  Google Scholar 

  36. Lynch, L. et al. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity 37, 574–587 (2012).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  37. Wen, H. et al. Fatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  38. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  39. Larsen, C.M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    PubMed  CAS  Article  Google Scholar 

  40. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  41. Johnston, R.A. et al. Diet-induced obesity causes innate airway hyperresponsiveness to methacholine and enhances ozone-induced pulmonary inflammation. J. Appl. Physiol. 104, 1727–1735 (2008).

    PubMed  CAS  Article  Google Scholar 

  42. Williams, A.S. et al. Obesity and airway responsiveness: role of TNFR2. Pulm. Pharmacol. Ther. 26, 444–454 (2013).

    PubMed  CAS  Article  Google Scholar 

  43. Johnston, R.A. et al. Allergic airway responses in obese mice. Am. J. Respir. Crit. Care Med. 176, 650–658 (2007).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  44. Calixto, M.C. et al. Obesity enhances eosinophilic inflammation in a murine model of allergic asthma. Br. J. Pharmacol. 159, 617–625 (2010).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  45. Kudo, M. et al. IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat. Med. 18, 547–554 (2012).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  46. McKinley, L. et al. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J. Immunol. 181, 4089–4097 (2008).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  47. Wakashin, H. et al. IL-23 and TH17 cells enhance TH2-cell–mediated eosinophilic airway inflammation in mice. Am. J. Respir. Crit. Care Med. 178, 1023–1032 (2008).

    PubMed  CAS  Article  Google Scholar 

  48. Lajoie, S. et al. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat. Immunol. 11, 928–935 (2010).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  49. Murdoch, J.R. & Lloyd, C.M. Resolution of allergic airway inflammation and airway hyperreactivity is mediated by IL-17–producing γδ T cells. Am. J. Respir. Crit. Care Med. 182, 464–476 (2010).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  50. Naik, S. et al. Compartmentalized control of skin immunity by resident commensals. Science 337, 1115–1119 (2012).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  51. Gross, O., Thomas, C.J., Guarda, G. & Tschopp, J. The inflammasome: an integrated view. Immunol. Rev. 243, 136–151 (2011).

    PubMed  CAS  Article  Google Scholar 

  52. Eisenbarth, S.C., Colegio, O.R., O'Connor, W., Sutterwala, F.S. & Flavell, R.A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  53. Besnard, A.G. et al. NLRP3 inflammasome is required in murine asthma in the absence of aluminum adjuvant. Allergy 66, 1047–1057 (2011).

    PubMed  CAS  Article  Google Scholar 

  54. Allen, I.C. et al. Analysis of NLRP3 in the development of allergic airway disease in mice. J. Immunol. 188, 2884–2893 (2012).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  55. Kool, M. et al. An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma. Immunity 34, 527–540 (2011).

    PubMed  CAS  Article  Google Scholar 

  56. Marichal, T. et al. DNA released from dying host cells mediates aluminum adjuvant activity. Nat. Med. 17, 996–1002 (2011).

    PubMed  CAS  Article  Google Scholar 

  57. Crellin, N.K. et al. Regulation of cytokine secretion in human CD127+ LTi-like innate lymphoid cells by Toll-like receptor 2. Immunity 33, 752–764 (2010).

    PubMed  CAS  Article  Google Scholar 

  58. Winer, S. et al. Obesity predisposes to TH17 bias. Eur. J. Immunol. 39, 2629–2635 (2009).

    PubMed  CAS  Article  Google Scholar 

  59. Fantuzzi, G. Adipose tissue, adipokines and inflammation. J. Allergy Clin. Immunol. 115, 911–919, quiz 920 (2005).

    PubMed  CAS  Article  Google Scholar 

  60. Kim, H.Y., DeKruyff, R.H. & Umetsu, D.T. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat. Immunol. 11, 577–584 (2010).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  61. Nakae, S. et al. Antigen-specific T cell sensitization is impaired in IL-17–deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375–387 (2002).

    PubMed  CAS  Article  Google Scholar 

  62. Sutterwala, F.S. et al. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24, 317–327 (2006).

    PubMed  CAS  Article  Google Scholar 

  63. McKenzie, G.J., Fallon, P.G., Emson, C.L., Grencis, R.K. & McKenzie, A.N. Simultaneous disruption of interleukin (IL)-4 and IL-13 defines individual roles in T helper cell type 2-mediated responses. J. Exp. Med. 189, 1565–1572 (1999).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  64. Akbari, O. et al. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat. Med. 9, 582–588 (2003).

    PubMed  CAS  Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Dale T Umetsu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Table 1 (PDF 2506 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3423

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing