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IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction

Nature Medicine volume 18, pages 547–554 (2012)Cite this article

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Abstract

Emerging evidence suggests that the T helper 17 (TH17) subset of αβ T cells contributes to the development of allergic asthma. In this study, we found that mice lacking the αvβ8 integrin on dendritic cells did not generate TH17 cells in the lung and were protected from airway hyper-responsiveness in response to house dust mite and ovalbumin sensitization and challenge. Because loss of TH17 cells inhibited airway narrowing without any obvious effects on airway inflammation or epithelial morphology, we examined the direct effects of TH17 cytokines on mouse and human airway smooth muscle function. Interleukin-17A (IL-17A), but not IL-17F or IL-22, enhanced contractile force generation of airway smooth muscle through an IL-17 receptor A (IL-17RA)–IL-17RC, nuclear factor κ light-chain enhancer of activated B cells (NF-κB)–ras homolog gene family, member A (RhoA)–Rho-associated coiled-coil containing protein kinase 2 (ROCK2) signaling cascade. Mice lacking integrin αvβ8 on dendritic cells showed impaired activation of this pathway after ovalbumin sensitization and challenge, and the diminished contraction of the tracheal rings in these mice was reversed by IL-17A. These data indicate that the IL-17A produced by TH17 cells contributes to allergen-induced airway hyper-responsiveness through direct effects on airway smooth muscle.

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Figure 1: Itgb8flox/flox; CD11c-Cre mice are protected from AHR and do not develop TH17 cells in the lung.
Figure 2: IL-17A enhances mouse and human ASM contraction.
Figure 3: IL-17A–mediated enhanced ASM contraction is not caused by contaminants or TNF-α release.
Figure 4: IL-17A activates NF-κB–RhoA-ROCK2 signaling in ASM.
Figure 5: IL-17F and IL-22 do not enhance ASM contraction, and IL-17A signals through IL-17RC.
Figure 6: Impaired activation of an IL-17A signaling pathway in Itgb8flox/flox; CD11c-Cre mice.

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) grants HL64353, HL53949, HL083950, AI024674 and U19 AI077439 (to D.S.), a NIH Ruth L. Kirschstein National Research Service Award HL095314 (to A.C.M.), an American Lung Association of California Research Training Fellowship Award (to A.C.M.) and funds from the University of California, San Francisco (UCSF) Strategic Asthma Basic Research Center. Deidentified human lung was kindly provided by M. Matthay (UCSF) and P. Wolters (UCSF). IL-17RC knockout mice were kindly provided by W. Ouyang (Genentech).

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  1. Makoto Kudo, Andrew C Melton, Xiaozhu Huang and Dean Sheppard: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Lung Biology Center, University of California, San Francisco, California, USA

    Makoto Kudo, Andrew C Melton, Chun Chen, Katherine E Huang, Xin Ren, Yanli Wang, Xin Bernstein, John T Li, Kamran Atabai, Xiaozhu Huang & Dean Sheppard

  2. Department of Internal Medicine and Clinical Immunology, Yokohama City University, Graduate School of Medicine, Kanazawa, Yokohama, Japan

    Makoto Kudo

  3. Department of Physiological Nursing, University of California, San Francisco, California, USA

    Mary B Engler

  4. Department of Pediatrics, University of California, San Francisco, California, USA

    John T Li

  5. Cardiovascular Research Institute, University of California, San Francisco, California, USA

    Kamran Atabai

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Contributions

M.K. designed the study, generated all of the tracheal ring contraction and western blot data, performed analyses and wrote the manuscript. A.C.M. designed the study, generated all of the flow cytometry and recall data, performed analyses and wrote the manuscript. C.C. generated all of the lung slice data, performed analyses and wrote the manuscript. K.E.H., X.R., Y.W. and X.B. performed the asthma physiology studies. M.B.E. designed and constructed the muscle bath and provided expertise in the methodology and modifications for the analysis of mouse tracheal ring contraction. J.T.L. and K.A. provided substantial intellectual contribution. X.H. and D.S. oversaw the design and interpretation of all studies described and oversaw the writing of the manuscript.

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Correspondence to Dean Sheppard.

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The authors declare no competing financial interests.

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Kudo, M., Melton, A., Chen, C. 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). https://doi.org/10.1038/nm.2684

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