Chen Xiaoli, Zhu Yuanfeng, Xia Lin, Su Sen, Fan Shijun, Lu Yongling, Chen Qian, Wei Yan, Huang Qianying, Liu Xin, Peng Xi
Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
State Key Laboratory of Trauma and Chemical Poisoning, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
FEBS J. 2025 Apr 28. doi: 10.1111/febs.70119.
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 IRG1/itaconate axis that suppresses the NLRP3 inflammasome. Furthermore, glutamine deficiency was detected in a murine sepsis model, whereas extrinsic glutamine supplementation conferred protection against intestinal inflammation and tissue damage in septic mice. Taken together, our findings provide a novel insight into the link between glutamine metabolism and NLRP3 inflammasome activation, highlighting the target of glutamine metabolism, which holds as a potential therapeutic strategy for inflammatory diseases.
含NACHT、LRR和PYD结构域的蛋白3（NLRP3）炎性小体的异常激活会增加成熟促炎细胞因子白细胞介素（IL）-1β和IL-18的释放，并增强细胞焦亡；因此需要对NLRP3炎性小体进行严格调控。功能失调的谷氨酰胺代谢参与多种炎症性疾病的发病机制，其确切机制仍有待阐明。在此，我们提供证据表明谷氨酰胺剥夺可增强巨噬细胞中NLRP3炎性小体的激活。事实上，缺乏外源性谷氨酰胺会特异性增强NLRP3炎性小体的组装，从而加速细胞焦亡并促进IL-1β和IL-18的成熟。抑制谷氨酰胺分解表现出与谷氨酰胺剥夺类似的效果，而这种效果可被α-酮戊二酸（α-KG）逆转，α-KG是一种三羧酸（TCA）循环中间体，可通过谷氨酰胺供应进行补充。我们进一步观察到谷氨酰胺剥夺会减少内源性衣康酸的生成，并证实外源性补充衣康酸衍生物以及通过过表达免疫反应基因1[IRG1；也称为乌头酸脱羧酶1（ACOD1）]增加内源性衣康酸的产生均可替代谷氨酰胺来抑制NLRP3炎性小体。从机制上讲，谷氨酰胺剥夺减少了底物来源，并抑制了转录因子EB（TFEB）依赖的IRG1转录上调，从而损害了抑制NLRP3炎性小体的IRG1/衣康酸轴。此外，在小鼠脓毒症模型中检测到谷氨酰胺缺乏，而外源性补充谷氨酰胺可保护脓毒症小鼠免受肠道炎症和组织损伤。综上所述，我们的研究结果为谷氨酰胺代谢与NLRP3炎性小体激活之间的联系提供了新的见解，突出了谷氨酰胺代谢这一靶点，有望成为炎症性疾病的潜在治疗策略。
