炎症体
吡喃结构域
细胞生物学
脂多糖
调节器
目标2
内生
化学
上睑下垂
启动(农业)
刺激
一氧化氮
程序性细胞死亡
炎症
受体
生物
生物化学
免疫学
细胞凋亡
神经科学
有机化学
基因
发芽
植物
作者
Monika Bambousková,Lucie Potůčková,Tomáš Paulenda,Martina Kerndl,Denis A. Mogilenko,Kate Lizotte,Amanda Swain,Sebastian Hayes,Ryan D. Sheldon,Hyeryun Kim,Unnati Kapadnis,Abigail E. Ellis,Christine Isaguirre,Samantha Burdess,Anwesha Laha,Gaya K. Amarasinghe,Victor Chubukov,Thomas P. Roddy,Michael Diamond,Russell G. Jones,Donald M. Simons,Maxim N. Artyomov
出处
期刊:Cell Reports
[Elsevier]
日期:2021-03-01
卷期号:34 (10): 108756-108756
被引量:147
标识
DOI:10.1016/j.celrep.2021.108756
摘要
Itaconate is a unique regulatory metabolite that is induced upon Toll-like receptor (TLR) stimulation in myeloid cells. Here, we demonstrate major inflammatory tolerance and cell death phenotypes associated with itaconate production in activated macrophages. We show that endogenous itaconate is a key regulator of the signal 2 of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation after long lipopolysaccharide (LPS) priming, which establishes tolerance to late NLRP3 inflammasome activation. We show that itaconate acts synergistically with inducible nitric oxide synthase (iNOS) and that the ability of various TLR ligands to establish NLRP3 inflammasome tolerance depends on the pattern of co-expression of IRG1 and iNOS. Mechanistically, itaconate accumulation upon prolonged inflammatory stimulation prevents full caspase-1 activation and processing of gasdermin D, which we demonstrate to be post-translationally modified by endogenous itaconate. Altogether, our data demonstrate that metabolic rewiring in inflammatory macrophages establishes tolerance to NLRP3 inflammasome activation that, if uncontrolled, can result in pyroptotic cell death and tissue damage.
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