Glutamine limits NLRP3 inflammasome activation and pyroptosis in macrophages by sustaining the IRG1 /itaconate axis

作者：Xiaoli Chen, Yuanfeng Zhu, Lin Xia, Sen Su, Shijun Fan, Yongling Lu, Qian Chen, Wei Yan, Qianying Huang, Xin Liu, Xi Peng · 发表于：FEBS Journal · 年份：2025 · DOI：10.1111/febs.70119 · 被引用次数：11 · 研究领域：Inflammasome and immune disorders、Congenital Diaphragmatic Hernia Studies、Heme Oxygenase-1 and Carbon Monoxide

Aberrant activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome increases the release of mature pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and enhances pyroptosis; thereby necessitating tight regulation of the NLRP3 inflammasome. Dysfunctional glutamine metabolism contributes to the pathogenesis of multiple inflammatory disorders, and the precise mechanism remains to be elucidated. Here, we provide evidence that glutamine deprivation enhances NLRP3 inflammasome activation in macrophages. Indeed, the absence of exogenous glutamine specifically enhanced NLRP3 inflammasome assembly, thereby accelerating pyroptosis and promoting the maturation of IL-1β and IL-18. Inhibition of glutaminolysis exhibited a similar effect to glutamine deprivation, whereas this effect was reversed by α-ketoglutarate (α-KG), a tricarboxylic acid (TCA)-cycle intermediate that can be replenished by glutamine supply. We further observed reduced generation of endogenous itaconate by glutamine deprivation and verified that both exogenous supplementation of itaconate derivative and increased endogenous itaconate production by overexpressing immune-responsive gene 1 [IRG1; also known as aconitate decarboxylase 1 (ACOD1)] could replace glutamine to inhibit the NLRP3 inflammasome. Mechanistically, glutamine deprivation decreased the source of substrate and inhibited transcription factor EB (TFEB)-dependent transcriptional upregulation of IRG1, thereby impairing the IR...