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.
Highlights
The NLRP3 inflammasome can sense different pathogens or danger signals, and has been reported to be involved in the development of many human diseases
To assess the function of chloride intracellular channels (CLIC) in NLRP3 inflammasome activation, we first examined whether indanyloxyacetic acid-94 (IAA94), which has shown inhibitory activity for CLICs39, could inhibit NLRP3 inflammasome activation
When LPS-primed bone marrow-derived macrophages (BMDMs) were pretreated with IAA94 before nigericin challenge, caspase-1 activation and IL-1β maturation were suppressed by IAA94 in a dose-dependent manner (Fig. 1a, b), while the production of TNF, an inflammasome-independent cytokine, was not affected (Fig. 1c)
Summary
The NLRP3 inflammasome can sense different pathogens or danger signals, and has been reported to be involved in the development of many human diseases. We show that chloride intracellular channels (CLIC) act downstream of the potassium efflux-mitochondrial reactive oxygen species (ROS) axis to promote NLRP3 inflammasome activation. The NLRP3 inflammasome is an intracellular protein complex formed by the innate immune sensor protein NLRP3, adapter protein ASC, and proteolysis enzyme caspase-11, 2 This protein complex is assembled in response to microbial infection or various non-infectious stresses to promote the cleavage and activation of caspase-1, which induces the maturation and secretion of proinflammatory cytokines, such as IL-1β and IL-183–5. Reactive oxygen species (ROS) production, lysosome damage, or disturbance of intracellular ion homeostasis have been proposed for mediating NLRP3 activation by the above agonists[3, 12, 13], how these signaling events orchestrate NLRP3 inflammasome activation is still poorly understood. How chloride current regulates NLRP3 inflammasome activation is unclear
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