Abstract
To understand the pathogenesis of chronic inflammatory disease, we analyzed an experimental mouse model of chronic lung disease with pathology that resembles asthma and chronic obstructive pulmonary disease (COPD) in humans. In this model, chronic lung disease develops after an infection with a common type of respiratory virus is cleared to only trace levels of noninfectious virus. Chronic inflammatory disease is generally thought to depend on an altered adaptive immune response. However, here we find that this type of disease arises independently of an adaptive immune response and is driven instead by interleukin-13 produced by macrophages that have been stimulated by CD1d-dependent T cell receptor–invariant natural killer T (NKT) cells. This innate immune axis is also activated in the lungs of humans with chronic airway disease due to asthma or COPD. These findings provide new insight into the pathogenesis of chronic inflammatory disease with the discovery that the transition from respiratory viral infection into chronic lung disease requires persistent activation of a previously undescribed NKT cell–macrophage innate immune axis.
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Acknowledgements
We thank T. Wynn (National Institute of Allergy and Infectious Diseases, Bethesda, Maryland) for Il13−/− mice, A. Bendelac (University of Chicago, Chicago, Illinois) for Cd1d1−/− mice, M. Taguchi (RIKEN, Yokohama, Japan) for Traj18−/− mice and S. Goldman (Wyeth Pharmaceuticals) for sIL-13Rα2-Fc. We thank W. Eades, C. Holley and J. Hughes in the Siteman Cancer Center High Speed Cell Sorter Core Facility and J. Jung and K. Dolim at Roche Palo Alto for technical assistance. This work was supported by grants from the US National Institutes of Health (Heart, Lung, and Blood Institute, Cancer Institute, and Institute of Allergy and Infectious Diseases), Barnes-Jewish Hospital Foundation, Martin Schaeffer Fund and Alan A. and Edith L. Wolff Charitable Trust.
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E.Y.K. conducted mouse model experiments; J.T.B. conducted human sample experiments; A.C.P. conducted bioinformatics analysis; Y.Y. conducted coculture experiments; E.A. generated viral preparations and titering reagents; M.H.G. assisted in flow cytometry experiments; L.A.B. assisted in NKT cell experiments; D.E.B. assisted in flow cytometry experiments; Y.A. established PCR assays; J.T. performed PCR assays; S.S. performed airway reactivity measurements; R.T. performed viral titer experiments; J.W.T. and J.D.M. assisted in mouse model experiments; M.C. provided asthma patient samples; D.P. assisted in human sample experiments; G.A.P. provided human COPD samples; R.A.S. provided liposome preparations; J.D.A. assisted in bioinformatic analysis; G.P. conducted microarray experiments; and M.J.H. conducted overall design of the project and construction of the article.
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Kim, E., Battaile, J., Patel, A. et al. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med 14, 633–640 (2008). https://doi.org/10.1038/nm1770
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DOI: https://doi.org/10.1038/nm1770
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