Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China; Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, China.
Department of Biochemistry, School of Life Sciences of Central South University, Changsha, China.
Biochem Pharmacol. 2022 Jul;201:115077. doi: 10.1016/j.bcp.2022.115077. Epub 2022 May 10.
Vascular and immune dysfunctions are thought to be related to the pathogenesis of inflammatory bowel disease (IBD), but behind this, the exact mechanism of mucosal vascular endothelial barrier dysfunction and macrophage phenotypic transition is not fully understood. Here, we explored the mechanistic role of sphingosine 1-phosphate receptor 2 (S1PR2) and its downstream G protein RhoA/Rho kinase 1 (ROCK1) signaling pathway in the intestinal endothelial barrier damage and M1 macrophage polarization in IBD. We found that the expression of S1PR2 in intestinal mucosal vascular endothelial cells and macrophages of IBD patients and DSS-induced colitis mice as well as vascular endothelial cells and macrophages treated with LPS in vitro was significantly increased. Knocking down or pharmacologically inhibiting S1PR2 significantly downregulated the expression of RhoA and ROCK1 in vascular endothelial cells and macrophages. Furthermore, inhibition of S1PR2 and ROCK1 reversed the impaired vascular barrier function and M1 macrophage polarization in vivo and in vitro, while reducing ER stress in vascular endothelial cells and glycolysis in macrophages. In addition, inhibition of ER stress or glycolysis reversed LPS-induced impairment of vascular endothelial cell barrier function and M1 macrophage polarization. Collectively, our results indicate that the S1PR2/RhoA/ROCK1 signaling pathway may participate in the pathogenesis of IBD by regulating vascular endothelial barrier function and M1 macrophage polarization.
血管和免疫功能障碍被认为与炎症性肠病（IBD）的发病机制有关，但在这背后，黏膜血管内皮屏障功能障碍和巨噬细胞表型转变的确切机制尚不完全清楚。在这里，我们探讨了鞘氨醇 1-磷酸受体 2（S1PR2）及其下游 G 蛋白 RhoA/Rho 激酶 1（ROCK1）信号通路在 IBD 中肠道内皮屏障损伤和 M1 巨噬细胞极化中的作用机制。我们发现，IBD 患者和 DSS 诱导的结肠炎小鼠的肠道黏膜血管内皮细胞和巨噬细胞以及体外用 LPS 处理的血管内皮细胞和巨噬细胞中 S1PR2 的表达明显增加。敲低或药理学抑制 S1PR2 可显著下调血管内皮细胞和巨噬细胞中 RhoA 和 ROCK1 的表达。此外，抑制 S1PR2 和 ROCK1 可逆转体内和体外血管屏障功能障碍和 M1 巨噬细胞极化，同时减少血管内皮细胞中的内质网应激和巨噬细胞中的糖酵解。此外，抑制内质网应激或糖酵解可逆转 LPS 诱导的血管内皮细胞屏障功能障碍和 M1 巨噬细胞极化。综上所述，我们的结果表明，S1PR2/RhoA/ROCK1 信号通路可能通过调节血管内皮屏障功能和 M1 巨噬细胞极化参与 IBD 的发病机制。
