Influenza virus activates inflammasomes via its intracellular M2 ion channel

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Abstract
The mechanism by which influenza virus activates the NLRP3 inflammasome is unknown. Iwasaki and colleagues show that the influenza virus M2 protein, a proton-selective ion channel, stimulates the NLRP3 inflammasome pathway. 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.