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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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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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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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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DOI: https://doi.org/10.1038/nm.2684
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