Critical role for calcium mobilization in activation of the NLRP3 inflammasome

TLDR

The NLRP3 inflammasome drives IL‑1β and IL‑18 production and is implicated in infection, sepsis, autoinflammatory and metabolic diseases, yet its proximal activation steps remain poorly understood. Here we elucidate a critical role for Ca²⁺ mobilization in activation of the NLRP3 inflammasome by multiple stimuli. C/EPB homologous protein, a transcription factor that modulates Ca²⁺ release from the ER, amplifies NLRP3 inflammasome activation, linking ER stress to inflammasome activation. Blocking Ca²⁺ mobilization inhibits NLRP3 assembly and activation, and during ATP stimulation Ca²⁺ signaling promotes mitochondrial damage, supporting a model that Ca²⁺‑mediated mitochondrial damage drives inflammasome activation.

Abstract

The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome mediates production of inflammatory mediators, such as IL-1β and IL-18, and as such is implicated in a variety of inflammatory processes, including infection, sepsis, autoinflammatory diseases, and metabolic diseases. The proximal steps in NLRP3 inflammasome activation are not well understood. Here we elucidate a critical role for Ca 2+ mobilization in activation of the NLRP3 inflammasome by multiple stimuli. We demonstrate that blocking Ca 2+ mobilization inhibits assembly and activation of the NLRP3 inflammasome complex, and that during ATP stimulation Ca 2+ signaling is pivotal in promoting mitochondrial damage. C/EPB homologous protein, a transcription factor that can modulate Ca 2+ release from the endoplasmic reticulum, amplifies NLRP3 inflammasome activation, thus linking endoplasmic reticulum stress to activation of the NLRP3 inflammasome. Our findings support a model for NLRP3 inflammasome activation by Ca 2+ -mediated mitochondrial damage.