Chunmiao Hu , Xiaoli He , Huimin Zhang , Xiangyu Hu , Liting Liao , Minmin Cai , Zhijie Lin , Jie Xiang , Xiaoqin Jia , Guotao Lu , Weiming Xiao , Yisheng Feng , Weijuan Gong
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Intraperitoneal injection of Tan I (4 mg/kg) effectively alleviated DSS-induced colitis in mice, accompanying with suppressing the activation of intestinal macrophages. Mechanistically, Tan I-treated macrophages exhibited a decrease in cytoplasmic ROS, NLRP3, GSDMD, and IL-1β, which suggested that the alternative pathway of inflammasome activation in macrophages was suppressed. The SPR assay demonstrated that Tan I bound to Syk protein with a dissociation constant (KD) of 2.473 × 10<sup>−6</sup> M. When Syk expression was knocked down by its shRNA, the inhibitory effects of Tan I on macrophages were blocked. Collectively, Tanshinone I effectively alleviated DSS-induced colitis in mice by inhibiting Syk-stimulated inflammasome activation, hence suppressing the inflammatory activity of macrophages.</p></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"173 ","pages":"Pages 88-98"},"PeriodicalIF":3.2000,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Tanshinone I limits inflammasome activation of macrophage via docking into Syk to alleviate DSS-induced colitis in mice\",\"authors\":\"Chunmiao Hu , Xiaoli He , Huimin Zhang , Xiangyu Hu , Liting Liao , Minmin Cai , Zhijie Lin , Jie Xiang , Xiaoqin Jia , Guotao Lu , Weiming Xiao , Yisheng Feng , Weijuan Gong\",\"doi\":\"10.1016/j.molimm.2024.07.007\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Tanshinone I (Tan I) has been proven to exert an anti-inflammatory effect, but the complete mechanism remains unclear. 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The SPR assay demonstrated that Tan I bound to Syk protein with a dissociation constant (KD) of 2.473 × 10<sup>−6</sup> M. When Syk expression was knocked down by its shRNA, the inhibitory effects of Tan I on macrophages were blocked. 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引用次数: 0
摘要
丹参酮 I(Tan I)已被证实具有抗炎作用,但其完整机制仍不清楚。这项研究表明,丹参酮 I 对静息或 LPS 刺激的巨噬细胞中 Syk 的表达没有影响,但能显著抑制巨噬细胞中 Syk 的磷酸化以及 CD80、CD86 和 IL-1β 的表达。Syk激活会上调载脂蛋白C3转基因(ApoC3)小鼠巨噬细胞的炎症活性。腹腔注射 Tan I(4 毫克/千克)可有效缓解 DSS 诱导的小鼠结肠炎,同时抑制肠道巨噬细胞的活化。从机理上讲,经 Tan I 处理的巨噬细胞表现出细胞质 ROS、NLRP3、GSDMD 和 IL-1β 的减少,这表明巨噬细胞中的炎性体活化替代途径受到了抑制。SPR 分析表明,Tan I 与 Syk 蛋白结合的解离常数(KD)为 2.473 × 10 M。当用 shRNA 敲低 Syk 表达时,丹参酮 I 对巨噬细胞的抑制作用被阻断。综上所述,丹参酮 I 通过抑制 Syk 刺激的炎性体活化,从而抑制巨噬细胞的炎症活性,有效缓解了 DSS 诱导的小鼠结肠炎。
Tanshinone I limits inflammasome activation of macrophage via docking into Syk to alleviate DSS-induced colitis in mice
Tanshinone I (Tan I) has been proven to exert an anti-inflammatory effect, but the complete mechanism remains unclear. In this study, Tan I was described to have no effect on Syk expression in resting or LPS-stimulated macrophages ex vivo, but dramatically suppressed Syk phosphorylation and CD80, CD86, and IL-1β expression of macrophages. The inflammatory activity of macrophages in ApoC3-transgenic (ApoC3TG) mice is upregulated by Syk activation. Tan I was determined to downregulate Syk phosphorylation and inflammatory activity of macrophages in ApoC3TG mice, both ex vivo and in vivo. Intraperitoneal injection of Tan I (4 mg/kg) effectively alleviated DSS-induced colitis in mice, accompanying with suppressing the activation of intestinal macrophages. Mechanistically, Tan I-treated macrophages exhibited a decrease in cytoplasmic ROS, NLRP3, GSDMD, and IL-1β, which suggested that the alternative pathway of inflammasome activation in macrophages was suppressed. The SPR assay demonstrated that Tan I bound to Syk protein with a dissociation constant (KD) of 2.473 × 10−6 M. When Syk expression was knocked down by its shRNA, the inhibitory effects of Tan I on macrophages were blocked. Collectively, Tanshinone I effectively alleviated DSS-induced colitis in mice by inhibiting Syk-stimulated inflammasome activation, hence suppressing the inflammatory activity of macrophages.
期刊介绍:
Molecular Immunology publishes original articles, reviews and commentaries on all areas of immunology, with a particular focus on description of cellular, biochemical or genetic mechanisms underlying immunological phenomena. Studies on all model organisms, from invertebrates to humans, are suitable. Examples include, but are not restricted to:
Infection, autoimmunity, transplantation, immunodeficiencies, inflammation and tumor immunology
Mechanisms of induction, regulation and termination of innate and adaptive immunity
Intercellular communication, cooperation and regulation
Intracellular mechanisms of immunity (endocytosis, protein trafficking, pathogen recognition, antigen presentation, etc)
Mechanisms of action of the cells and molecules of the immune system
Structural analysis
Development of the immune system
Comparative immunology and evolution of the immune system
"Omics" studies and bioinformatics
Vaccines, biotechnology and therapeutic manipulation of the immune system (therapeutic antibodies, cytokines, cellular therapies, etc)
Technical developments.