title: Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria.
abstract: Interleukin-1beta (IL-1beta) is a pro-inflammatory cytokine that plays an important role in host defense and inflammatory diseases. The maturation and secretion of IL-1beta are mediated by caspase-1, a protease that processes pro-IL-1beta into biologically active IL-1beta. The activity of caspase-1 is controlled by the inflammasome, a multiprotein complex formed by NLR proteins and the adaptor ASC, that induces the activation of caspase-1. The current model proposes that changes in the intracellular concentration of K(+) potentiate caspase-1 activation induced by the recognition of bacterial products. However, the roles of P2X7 receptor and intracellular K(+) in IL-1beta secretion induced by bacterial infection remain unknown. Here we show that, in response to Toll-like receptor agonists such as lipopolysaccharide or infection with extracellular bacteria Staphylococcus aureus and Escherichia coli, efficient caspase-1 activation is only triggered by addition of ATP, a signal that promotes caspase-1 activation through depletion of intracellular K(+) caused by stimulation of the purinergic P2X7 receptor. In contrast, activation of caspase-1 that relies on cytosolic sensing of flagellin or intracellular bacteria did not require ATP stimulation or depletion of cytoplasmic K(+). Consistently, caspase-1 activation induced by intracellular Salmonella or Listeria was unimpaired in macrophages deficient in P2X7 receptor. These results indicate that, unlike caspase-1 induced by Toll-like receptor agonists and ATP, activation of the inflammasome by intracellular bacteria and cytosolic flagellin proceeds normally in the absence of P2X7 receptor-mediated cytoplasmic K(+) perturbations.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Franchi
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.forename: George R
authors.initials: GR
authors.lastname: Dubyak
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001424:Bacterial Infections / Q000378:metabolism* / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism / Q000382:microbiology; D004927:Escherichia coli Infections / Q000378:metabolism / Q000503:physiopathology; D005110:Extracellular Space / Q000378:metabolism / Q000382:microbiology; D005408:Flagellin / Q000378:metabolism / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008088:Listeriosis / Q000378:metabolism / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008817:Mice, Mutant Strains; D011188:Potassium / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7; D012480:Salmonella Infections / Q000378:metabolism / Q000503:physiopathology; D012486:Salmonella typhimurium; D013203:Staphylococcal Infections / Q000378:metabolism / Q000503:physiopathology; D013211:Staphylococcus aureus
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; C512299:Ipaf protein, mouse; D008070:Lipopolysaccharides; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D005408:Flagellin; D000255:Adenosine Triphosphate; D020170:Caspase 1; D011188:Potassium