Abstract
Inflammasomes are cytosolic complexes that mature and secrete the inflammatory cytokines interleukin 1β (IL-1β) and IL-18 and induce pyroptosis. The NLRP3 (NACHT, LRR, and PYD domains–containing protein 3) inflammasome detects many pathogen- and danger-associated molecular patterns, and reactive oxygen species (ROS)/reactive nitrogen species (RNS) have been implicated in its activation. The phenazine pyocyanin (PCN) is a virulence factor of Pseudomonas aeruginosa and generates superoxide in cells. Here we report that PCN inhibits IL-1β and IL-18 release and pyroptosis upon NLRP3 inflammasome activation in macrophages by preventing speck formation and Caspase-1 maturation. Of note, PCN did not regulate the AIM2 (absent in melanoma 2) or NLRC4 inflammasomes or tumor necrosis factor (TNF) secretion. Imaging of the fluorescent glutathione redox potential sensor Grx1-roGFP2 indicated that PCN provokes cytosolic and nuclear but not mitochondrial redox changes. PCN-induced intracellular ROS/RNS inhibited the NLRP3 inflammasome posttranslationally, and hydrogen peroxide or peroxynitrite alone were sufficient to block its activation. We propose that cytosolic ROS/RNS inhibit the NLRP3 inflammasome and that PCN's anti-inflammatory activity may help P. aeruginosa evade immune recognition.
Highlights
Inflammasomes are cytosolic complexes that mature and secrete the inflammatory cytokines interleukin 1 (IL-1) and IL-18 and induce pyroptosis
We examined whether PCN interferes with inflammasome activation by nigericin at concentrations it has in the sputum of cystic fibrosis patients [13]
We show that PCN blocked activation of the NLRP3 inflammasome upstream of speck formation
Summary
We examined whether PCN interferes with inflammasome activation by nigericin at concentrations it has in the sputum of cystic fibrosis patients [13]. PCN rescued the cells from pyroptosis, as shown by the retention of intracellular LDH. PCN inhibited Caspase-1 processing and maturation of IL-1, both hallmarks of inflammasome activation (Fig. 1E). PCN did not affect the levels of pro-IL-1 or NLRP3 These data show that PCN inhibits Caspase-1 maturation and the release of IL-1 and IL-18 in response to various NLRP3 inflammasome activators. PCN did not rescue cells from NLRC4- or AIM2-dependent pyroptosis (Fig. 2B). PCN was not toxic, as shown by the retention of intracellular LDH (Fig. 2D). Together, these data show that PCN interferes with the NLRP3 inflammasome
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