炎症体
炎症
NLRC4型
目标2
化学
代谢物
细胞生物学
体内
生物化学
半胱氨酸蛋白酶1
生物
免疫学
生物技术
作者
Alexander Hooftman,Stefano Angiari,Svenja Hester,Sarah E. Corcoran,Marah C. Runtsch,Chris Ling,Melanie C. Ruzek,Peter F. Slivka,Anne F. McGettrick,Kathy Banahan,Mark Hughes,Alan D. Irvine,Román Fischer,Luke O'neill
出处
期刊:Cell Metabolism
[Elsevier]
日期:2020-08-12
卷期号:32 (3): 468-478.e7
被引量:347
标识
DOI:10.1016/j.cmet.2020.07.016
摘要
The Krebs cycle-derived metabolite itaconate is highly upregulated in inflammatory macrophages and exerts immunomodulatory effects through cysteine modifications on target proteins. The NLRP3 inflammasome, which cleaves IL-1β, IL-18, and gasdermin D, must be tightly regulated to avoid excessive inflammation. Here we provide evidence that itaconate modifies NLRP3 and inhibits inflammasome activation. Itaconate and its derivative, 4-octyl itaconate (4-OI), inhibited NLRP3 inflammasome activation, but not AIM2 or NLRC4. Conversely, NLRP3 activation was increased in itaconate-depleted Irg1−/− macrophages. 4-OI inhibited the interaction between NLRP3 and NEK7, a key step in the activation process, and "dicarboxypropylated" C548 on NLRP3. Furthermore, 4-OI inhibited NLRP3-dependent IL-1β release from PBMCs isolated from cryopyrin-associated periodic syndrome (CAPS) patients, and reduced inflammation in an in vivo model of urate-induced peritonitis. Our results identify itaconate as an endogenous metabolic regulator of the NLRP3 inflammasome and describe a process that may be exploited therapeutically to alleviate inflammation in NLRP3-driven disorders.
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