CLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation

Abstract

The NLRP3 inflammasome can sense different pathogens or danger signals, and has been reported to be involved in the development of many human diseases. Potassium efflux and mitochondrial damage are both reported to mediate NLRP3 inflammasome activation, but the underlying, orchestrating signaling events are still unclear. Here we show that chloride intracellular channels (CLIC) act downstream of the potassium efflux-mitochondrial reactive oxygen species (ROS) axis to promote NLRP3 inflammasome activation. NLRP3 agonists induce potassium efflux, which causes mitochondrial damage and ROS production. Mitochondrial ROS then induces the translocation of CLICs to the plasma membrane for the induction of chloride efflux to promote NEK7–NLRP3 interaction, inflammasome assembly, caspase-1 activation, and IL-1β secretion. Thus, our results identify CLICs-dependent chloride efflux as an essential and proximal upstream event for NLRP3 activation.

Metabolic regulation of NLRP3

“…Mitochondrial ROS has been shown to drive translocation of CLICs to the plasma membrane where they cause chloride efflux. The chloride efflux was then shown to drive NEK7‐NLRP3 activation . This study therefore provides a new insight into ROS as a driver of NLRP3.…”

“…The chloride efflux was then shown to drive NEK7-NLRP3 activation. 25 This study therefore provides a new insight into ROS as a driver of NLRP3. Interestingly, a known activating NLRP3 variant in cryopyrin-associated periodic syndrome (CAPS)-associated macrophages, R258W, also required NEK7 for chronic activation, independent of K + efflux.…”

Three Decades of Chloride Intracellular Channel Proteins: From Organelle to Organ Physiology

“…There are six mammalian CLIC paralogs and, under physiological conditions, the majority of the CLICs are present on intracellular organelles and in the cytoplasm (Singh, ; Ulmasov et al., ). In addition to intracellular organelle membranes, CLICs can associate with the plasma membrane (Averaimo, Milton, Duchen, & Mazzanti, ; Milton et al., ; Tang et al., ; Warton et al., ) under pathological conditions or upon overexpression. Information on the localization of CLICs is summarized in Figure .…”

LRRC8A regulates hypotonicity-induced NLRP3 inflammasome activation

“…RNAi knockdown of both CLIC1 and 4 impaired LPS and ATP-induced IL-1β release from macrophages (24). In addition to CLICs 1 and 4, CLIC5 is also implicated in NLRP3-dependent IL-1β release (25). Knockdown of CLICs 1, 4, and 5 inhibits NLRP3 inflammasome activation in response to the soluble agonists ATP and nigericin, and also the particulate DAMP monosodium urate crystals (25).…”

“…In addition to CLICs 1 and 4, CLIC5 is also implicated in NLRP3-dependent IL-1β release (25). Knockdown of CLICs 1, 4, and 5 inhibits NLRP3 inflammasome activation in response to the soluble agonists ATP and nigericin, and also the particulate DAMP monosodium urate crystals (25). Thus, it appears that multiple Clchannels encode diverse signals arising from DAMP stimulation, or from altered cellular homeostasis, to trigger NLRP3 inflammasome activation.…”