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免疫调节代谢产物衣康酸修饰NLRP3并抑制炎症小体活化
2020-08-14 17:47
来源：小柯机器人

爱尔兰三一学院Luke A.J. O’Neill研究团队发现免疫调节代谢产物衣康酸修饰NLRP3并抑制炎症小体活化。2020年8月12日，《细胞—代谢》在线发表了这一成果。

研究人员提供了衣康酸修饰NLRP3并抑制炎症小体激活的证据。衣康酸及其衍生物衣康酸4-辛酯（4-OI）能够抑制NLRP3炎性小体活化，但不抑制AIM2或NLRC4。相反，在缺衣康酸的Irg1-/-巨噬细胞中，NLRP3激活增加。4-OI抑制了NLRP3和NEK7之间的相互作用，这是激活过程中的关键步骤，并且抑制了NLRP3上“dicarboxypropylated” 修饰的C548。
 
此外，4-OI抑制了从冷冻蛋白相关周期性综合征（CAPS）患者分离的PBMC中NLRP3依赖性IL-1β的释放，并在尿酸盐诱发腹膜炎的体内模型中减少了炎症。这些结果确定衣康酸是NLRP3炎性小体的内源性代谢调节剂，并描述了一个可治疗性干预的炎症过程。
 
据悉，克雷布斯循环衍生的代谢物衣康酸在炎性巨噬细胞中高度上调，并通过半胱氨酸修饰靶蛋白发挥免疫调节作用。切割IL-1β、IL-18和Gasdermin D的NLRP3炎性小体必须严格控制，以避免过度炎症。
 
附：英文原文

Title: The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation

Author: 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 M. Hughes, Alan D. Irvine, Roman Fischer, Luke A.J. O’Neill

Issue&Volume: 2020-08-12

Abstract: 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.

DOI: 10.1016/j.cmet.2020.07.016

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30411-3

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
官方网址：https://www.cell.com/cell-metabolism/home
投稿链接：https://www.editorialmanager.com/cell-metabolism/default.aspx


本期文章：《细胞—代谢》：Online/在线发表

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