Dousing fire with gasoline: interplay between lysosome damage and the NLRP3 inflammasome. Focus on 'NLRP3 inflammasome signaling is activated by low-level lysosome disruption but inhibited by extensive lysosome disruption: roles for K~+ efflux and Ca~(2+) influx'

摘要

since its discovery over a decade ago, the NLRP3 inflammasome has been the focus of intense investigation. Although much has been learned about the molecular regulation of this potent inflammatory complex, there are several unanswered questions about what drives its assembly. At its simplest, the inflammasome is a cytosolic complex of proteins that functions to cleave and release the cytokines IL-1beta and IL-18 during inflammation. Inflammasome activation is tightly controlled and requires two distinct signals for complex activation and IL-1beta release. Signal 1 is a priming step typically delivered by Toll-like receptor activation, and signal 2 is a cytosolic stress signal that triggers assembly of a multiprotein complex that includes the molecules NLRP3, ASC, and caspase 1 (6). In the case of the NLRP3 inflammasome, signal 2 can come in many flavors including ATP-induced ion fluxes, mitochondrial oxidative stress, and lysosome damage (3). The diverse nature of signal 2 stimuli that promote NLRP3 inflammasome assembly suggests that common upstream pathways must be engaged. The precise mechanisms through which this occurs remain poorly understood.