Abstract
Lung epithelial cells can influence immune responses to airway allergens1,2. Airway epithelial cells also undergo apoptosis after encountering environmental allergens3; yet, relatively little is known about how these are cleared, and their effect on airway inflammation. Here we show that airway epithelial cells efficiently engulf apoptotic epithelial cells and secrete anti-inflammatory cytokines, dependent upon intracellular signalling by the small GTPase Rac1. Inducible deletion of Rac1 expression specifically in airway epithelial cells in a mouse model resulted in defective engulfment by epithelial cells and aberrant anti-inflammatory cytokine production. Intranasal priming and challenge of these mice with house dust mite extract or ovalbumin as allergens led to exacerbated inflammation, augmented Th2 cytokines and airway hyper-responsiveness, with decreased interleukin (IL)-10 in bronchial lavages. Rac1-deficient epithelial cells produced much higher IL-33 upon allergen or apoptotic cell encounter, with increased numbers of nuocyte-like cells1,4,5. Administration of exogenous IL-10 ‘rescued’ the airway inflammation phenotype in Rac1-deficient mice, with decreased IL-33. Collectively, these genetic and functional studies suggest a new role for Rac1-dependent engulfment by airway epithelial cells and in establishing the anti-inflammatory environment, and that defects in cell clearance in the airways could contribute to inflammatory responses towards common allergens.
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Acknowledgements
We thank the members of the Ravichandran laboratory for their suggestions, especially J. Kinchen and P. Trampont. We thank J. Whitsett for the rtTA-CCSP/Cre mice, X. Liu for the TGF-β responsive cell line PE25, and J. Steinke and J. Kennedy for providing human nasal epithelial cells. This work was supported by an Immunology Training Grant (I.J.J.), a F32 postdoctoral fellowship from the NHLBI (I.J.J.), and grants from the American Asthma Foundation and the National Institutes of Health (K.S.R.). K.S.R. has been a William Benter Senior Fellow of the American Asthma Foundation.
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I.J.J. designed, performed and analysed most of the experiments in this study with input from K.S.R. A.K. optimized and performed the isolations and ex vivo cultures of primary epithelial cells and the nitrotetrazoleum staining. A.K.S. performed the lung function analysis. Y.M.S. performed the airway hyper-responsiveness experiments to determine the degree of airway resistance. L.B. provided intellectual input on specific experiments and helped with the human tissue studies. I.J.J. and K.S.R. wrote the manuscript with comments from co-authors.
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Juncadella, I., Kadl, A., Sharma, A. et al. Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation. Nature 493, 547–551 (2013). https://doi.org/10.1038/nature11714
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DOI: https://doi.org/10.1038/nature11714
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