The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation
The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation
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DOI：
10.1016/j.cmet.2020.07.016
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发表时间：
2020-09-01
期刊：
影响因子：
29
通讯作者：
O'Neill, Luke A. J.
中科院分区：
文献类型：
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作者：
Hooftman, Alexander;Angiari, Stefano;O'Neill, Luke A. J.
克雷布斯循环衍生的代谢物衣康酸在炎症巨噬细胞中高度上调，并通过对靶蛋白的半胱氨酸修饰发挥免疫调节作用。切割IL-1 β、IL-18和gasdermin D的NLRP 3炎性体必须受到严格调控，以避免过度炎症。在这里，我们提供的证据表明衣康酸修饰NLRP 3和抑制炎性小体激活。衣康酸及其衍生物4-辛基衣康酸酯（4-OI）抑制NLRP 3炎性小体活化，但不抑制AIM 2或NLRC 4。相反，在衣康酸耗尽的Irg 1（-/-）巨噬细胞中NLRP 3活化增加。4-OI抑制NLRP 3和NEK 7之间的相互作用，这是活化过程中的关键步骤，并且NLRP 3上的“二羧基丙基化”C548。此外，4-OI抑制了从cryopyrin相关周期综合征（CAPS）患者分离的PBMC中NLRP 3依赖性IL-1 β的释放，并减少了尿酸盐诱导的腹膜炎体内模型中的炎症。我们的研究结果确定衣康酸作为NLRP 3炎性体的内源性代谢调节剂，并描述了一种可以在治疗上用于减轻NLRP 3驱动的疾病中的炎症的过程。
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-1 beta, 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-1 beta 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.