Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis

摘要

The common pathological manifestation of cystic fibrosis (CF) is associated with an excessive lung inflammatory response characterized by interleukin-1β accumulation. CF airway epithelial cells show an exacerbated pro-inflammatory response to Pseudomonas aeruginosa ; however, it is unclear whether this heightened inflammatory response is intrinsic to cells lacking CF transmembrane conductance regulator ( CFTR ). Here we demonstrate that the degree and quality of the inflammatory response in CF are supported by P. aeruginosa -dependent mitochondrial perturbation, in which flagellin is the inducer and mitochondrial Ca2+ uniporter ( MCU ) is a signal-integrating organelle member for NLRP3 activation and IL-1β and IL-18 processing. Our work elucidates the regulation of the NLRP3 inflammasome by mitochondrial Ca2+ in the P. aeruginosa -dependent inflammatory response and deepens our understanding of the significance of mitochondria in the Ca2+-dependent control of inflammation.