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

Nat Commun. 2015 Feb 4;6:6201. doi: 10.1038/ncomms7201.

Abstract

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 Ca(2+) 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 Ca(2+) in the P. aeruginosa-dependent inflammatory response and deepens our understanding of the significance of mitochondria in the Ca(2+)-dependent control of inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bronchi / metabolism
  • Bronchi / microbiology
  • Bronchi / pathology
  • Calcium / metabolism*
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Calcium Signaling
  • Carrier Proteins / agonists
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis / microbiology
  • Cystic Fibrosis / pathology
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Epithelial Cells / metabolism*
  • Epithelial Cells / microbiology
  • Epithelial Cells / pathology
  • Flagellin / genetics
  • Flagellin / metabolism
  • Gene Expression Regulation
  • Host-Pathogen Interactions
  • Humans
  • Inflammation
  • Interleukin-18 / biosynthesis
  • Interleukin-18 / metabolism
  • Interleukin-1beta / biosynthesis
  • Interleukin-1beta / metabolism
  • Mitochondria / metabolism*
  • Mitochondria / microbiology
  • Mitochondria / pathology
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Pseudomonas aeruginosa / pathogenicity
  • Pseudomonas aeruginosa / physiology*

Substances

  • CFTR protein, human
  • Calcium Channels
  • Carrier Proteins
  • Interleukin-18
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • mitochondrial calcium uniporter
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Flagellin
  • Calcium