Abstract
Influenza virus, a negative-stranded RNA virus that causes severe illness in humans and animals, stimulates the inflammasome through the Nod-like receptor NLRP3. However, the mechanism by which influenza virus activates the NLRP3 inflammasome is unknown. Here we show that the influenza virus M2 protein, a proton-selective ion channel important in viral pathogenesis, stimulates the NLRP3 inflammasome pathway. M2 channel activity was required for the activation of inflammasomes by influenza and was sufficient to activate inflammasomes in primed macrophages and dendritic cells. M2-induced activation of inflammasomes required its localization to the Golgi apparatus and was dependent on the pH gradient. Our results show a mechanism by which influenza virus infection activates inflammasomes and identify the sensing of disturbances in intracellular ionic concentrations as a previously unknown pathogen-recognition pathway.
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Acknowledgements
We thank Z.J. Chen (University of Texas Southwestern Medical Center) for MAVS-deficient mice; H. Hasegawa (National Institute of Infectious Diseases, Tokyo) for influenza virus strains A/Puerto Rico/8/34, A/Yamagata/120/86, A/Beijing/262/95, A/Aichi/2/68, A/Sydney/5/97 (subtype H3N2), A/Guizhou/54/89 × A/Puerto Rico/8/34 and B/Ibaraki/2/85; M.K. Collins (University College London) for lentiviral vector pHRSIN-CSGW (expressing GFP); R. Lamb (Northwestern University) for influenza virus A/Udorn/307/72 strain and the mutant virus M2del29–31; D. DiMaio (Yale University) for plasmids pT2H-HA-E5 and pT2H-HA-Q17G; C. Roy (Yale University) for GalNAc-T2-YFP BSC-1 cells; R. Medzhitov (Yale University) for monoclonal antibody 3ZD to IL-1β; M. Caplan, J. Kagan, I. Brodsky, W. Kee, E. Ip, H.K. Lee, Y. Yanagi and S. Ikegame for advice; and R. Medzhitov and J.M. Thompson for critical reading of the manuscript. Supported by the National Institutes of Health (AI062428, AI064705 and AI083242 to A.I.), the Japan Society for the Promotion of Science (T.I.) and Burroughs Wellcome (A.I.).
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T.I. and A.I. designed the experiments and prepared the manuscript; T.I. and I.K.P. did experiments; and T.I., I.K.P. and A.I. analyzed data.
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Ichinohe, T., Pang, I. & Iwasaki, A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat Immunol 11, 404–410 (2010). https://doi.org/10.1038/ni.1861
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DOI: https://doi.org/10.1038/ni.1861
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