Mitochondrial damage activates the NLRP10 inflammasome

Abstract Upon detecting pathogens or cell stress, several NOD-like receptors (NLRs) form inflammasome complexes with the adaptor ASC and caspase-1, inducing activation of IL-1β and IL-18, and gasdermin D-dependent cell death. The triggers and activation mechanisms of several inflammasome-forming sensors remain poorly understood. Here, we found that mitochondrial damage activates the NLRP10 inflammasome, leading to ASC speck formation and caspase-1-dependent cytokine release. Unlike AIM2, NLRP10 monitors mitochondrial integrity in a mitochondrial DNA-independent manner, suggesting the detection of distinct molecular entities displayed by the damaged organelles. NLRP10 is highly expressed in differentiated human keratinocytes, where it also senses mitochondrial damage. Our study reveals a novel inflammasome that surveils mitochondrial integrity, which could lead to further understanding of inflammatory diseases.