Hu Chunmiao, He Xiaoli, Zhang Huimin, Hu Xiangyu, Liao Liting, Cai Minmin, Lin Zhijie, Xiang Jie, Jia Xiaoqin, Lu Guotao, Xiao Weiming, Feng Yisheng, Gong Weijuan
Department of Gastroenterology, Yangzhou Key Laboratory for Precision Treatment of Refractory Bowel Diseases, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225001, PR China.
Kunshan Hospital of Traditional Chinese Medicine, Suzhou Key Laboratory of Integrated Traditional Chinese and Western Medicine of Digestive Diseases, Kunshan Affiliated Hospital of Yangzhou University, Kunshan, PR China.
Mol Immunol. 2024 Sep;173:88-98. doi: 10.1016/j.molimm.2024.07.007. Epub 2024 Jul 31.
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 (ApoC3) mice is upregulated by Syk activation. Tan I was determined to downregulate Syk phosphorylation and inflammatory activity of macrophages in ApoC3 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 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.
丹参酮I（Tan I）已被证明具有抗炎作用，但其完整机制仍不清楚。在本研究中，体外实验表明Tan 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的Syk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。体内外实验均表明，Tan I可下调ApoC3小鼠巨噬细胞的Syk磷酸化和炎症活性。腹腔注射Tan I（4mg/kg）可有效减轻小鼠DSS诱导的结肠炎，并抑制肠道巨噬细胞的激活。机制上，Tan I处理的巨噬细胞中细胞质ROS、NLRP3、GSDMD和IL-1β减少，这表明巨噬细胞中炎性小体激活的替代途径受到抑制。SPR分析表明，Tan I与Syk蛋白结合，解离常数（KD）为2.473×10 M。当通过shRNA敲低Syk表达时，Tan 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刺激的炎性小体激活，从而抑制巨噬细胞的炎症活性，有效减轻小鼠DSS诱导的结肠炎。
