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-1 beta 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-1 beta 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.