Kynurenic acid ameliorates NLRP3 inflammasome activation by blocking calcium mobilization via GPR35.
Kynurenic acid ameliorates NLRP3 inflammasome activation by blocking calcium mobilization via GPR35.
复制标题
犬尿酸通过 GPR35 阻断钙动员，改善 NLRP3 炎症小体激活
DOI：
10.3389/fimmu.2022.1019365
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发表时间：
2022
影响因子：
7.3
通讯作者：
Wang, Xuefu
中科院分区：
文献类型：
--
作者：
Sun, Tianyin;Xie, Ruiqian;He, Hongbin;Xie, Qianqian;Zhao, Xueqin;Kang, Guijie;Cheng, Chen;Yin, Wenwei;Cong, Jingjing;Li, Jing;Wang, Xuefu
炎性小体与多种炎症和代谢疾病有关，严格控制炎性小体的激活是必要的，以避免过度炎症。犬尿酸(KA)是犬尿氨酸途径中的色氨酸代谢物。然而，KA调节炎性小体激活的作用和机制尚未完全阐明。在这里，我们发现KA通过特异性地抑制NLRP3炎症体的典型和非典型激活而抑制巨噬细胞中caspase-1的激活和IL-1β的产生。在机制上，KA通过G蛋白受体35(GPR35)减少钙动员，导致线粒体损伤减少，mtROS产生减少，从而阻断NLRP3炎症体的组装和激活。重要的是，KA可预防脂多糖引起的全身炎症、尿酸单钠引起的腹膜炎症和高脂饮食引起的代谢紊乱。因此，KA通过阻断钙动员通过GPR35介导的NLRP3炎症体激活来改善炎症和代谢紊乱。我们的数据揭示了KA调节炎症体激活的新机制，并提示GPR35可能是通过调节钙动员来改善NLRP3炎症体相关疾病的一个有前途的靶点。
The inflammasome has been linked to diverse inflammatory and metabolic diseases, and tight control of inflammasome activation is necessary to avoid excessive inflammation. Kynurenic acid (KA) is a tryptophan metabolite in the kynurenine pathway. However, the roles and mechanisms of the regulation of inflammasome activation by KA have not yet been fully elucidated. Here, we found that KA suppressed caspase-1 activation and IL-1β production in macrophages by specifically inhibiting canonical and noncanonical activation of the NLRP3 inflammasome. Mechanistically, KA reduced calcium mobilization through G-protein receptor 35 (GPR35), resulting in reduced mitochondrial damage and decreased mtROS production, thus blocking NLRP3 inflammasome assembly and activation. Importantly, KA prevented lipopolysaccharide-induced systemic inflammation, monosodium urate-induced peritoneal inflammation, and high-fat diet-induced metabolic disorder. Thus, KA ameliorated inflammation and metabolic disorders by blocking calcium mobilization-mediated NLRP3 inflammasome activation via GPR35. Our data reveal a novel mechanism for KA in the modulation of inflammasome activation and suggest that GPR35 might be a promising target for improving NLRP3 inflammasome-associated diseases by regulating calcium mobilization.
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影响因子：
--
作者：
Pavillard LE;Cañadas-Lozano D;Alcocer-Gómez E;Marín-Aguilar F;Pereira S;Robertson AAB;Muntané J;Ryffel B;Cooper MA;Quiles JL;Bullón P;Ruiz-Cabello J;Cordero MD
通讯作者：
Cordero MD
影响因子：
4.2
作者：
Dudzinska, Ewa;Szymona, Kinga;Urbanska, Ewa M.
通讯作者：
Urbanska, Ewa M.
影响因子：
--
作者：
Quon T;Lin LC;Ganguly A;Tobin AB;Milligan G
通讯作者：
Milligan G
DOI：
10.4049/jimmunol.1202737
发表时间：
2013-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
He Y;Franchi L;Núñez G
通讯作者：
Núñez G
影响因子：
5.1
作者：
Oxenkrug GF
通讯作者：
Oxenkrug GF