Abstract
Patients with asthma, a major public health problem, are at high risk for serious disease from influenza virus infection, but the pathogenic mechanisms by which influenza A causes airway disease and asthma are not fully known. We show here in a mouse model that influenza infection acutely induced airway hyper-reactivity (AHR), a cardinal feature of asthma, independently of T helper type 2 (TH2) cells and adaptive immunity. Instead, influenza infection induced AHR through a previously unknown pathway that required the interleukin 13 (IL-13)–IL-33 axis and cells of the non-T cell, non-B cell innate lymphoid type called 'natural helper cells'. Infection with influenza A virus, which activates the NLRP3 inflammasome, resulted in much more production of IL-33 by alveolar macrophages, which in turn activated natural helper cells producing substantial IL-13.
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Acknowledgements
We thank M. Grusby (Harvard School of Public Health) for CD1d-deficient mice (backcrossed to the BALB/c strain) and Z. Luo for technical support. Supported by the US National Institutes of Health (R01 AI068085, R01 HL62348 and R01 051354).
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Y.-J.C. designed the study, did experiments, analyzed the data and wrote the manuscript; H.Y.K. did experiments and analyzed the data; L.A.A. did experiments; N.B. provided the H3N1 virus and did experiments. A.N.J.M., D.E.S. and R.H.D. provided reagents and ST2-deficient (Il1rl1−/−) and IL-13 deficient (Il13−/−) mice; and D.T.U. designed the study and wrote the manuscript.
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D.E.S. is an employee and shareholder of Amgen.
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Chang, YJ., Kim, H., Albacker, L. et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol 12, 631–638 (2011). https://doi.org/10.1038/ni.2045
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DOI: https://doi.org/10.1038/ni.2045
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