Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cell Rep. 2021 Mar 9;34(10):108756. doi: 10.1016/j.celrep.2021.108756.
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.
衣康酸是一种独特的调节代谢物，在髓系细胞中受到 Toll 样受体 (TLR) 刺激后会被诱导产生。在这里，我们证明了在激活的巨噬细胞中产生衣康酸与炎症反应耐受和细胞死亡表型密切相关。我们发现内源性衣康酸是 NLR 家族包含 pyrin 结构域 3 (NLRP3) 炎症小体激活信号 2 的关键调节剂，它在长时间脂多糖 (LPS) 引发后建立对晚期 NLRP3 炎症小体激活的耐受。我们发现衣康酸与诱导型一氧化氮合酶 (iNOS) 协同作用，并且各种 TLR 配体建立 NLRP3 炎症小体耐受的能力取决于 IRG1 和 iNOS 的共表达模式。从机制上讲，在长期炎症刺激下积累的衣康酸会阻止半胱天冬酶-1的完全激活和 Gasdermin D 的加工，我们证明 Gasdermin D 被内源性衣康酸进行了翻译后修饰。总的来说，我们的数据表明，炎症反应巨噬细胞中的代谢重编程建立了对 NLRP3 炎症小体激活的耐受，如果不受控制，可能导致细胞发生细胞焦亡和组织损伤。
