Siglec-E在脓毒症单核巨噬细胞极化中的作用及调节机制

Macrophage polarization, as a major participant of immune dysfunction in sepsis, has an ambiguous pathogenesis until now. Siglec-E is a molecular mostly expressed on the surface of macrophage, and our previous study showed that Siglec-E on macrophages in sepsis was up-regulated, and the survival of septic mice decreased when the expression of Siglec-E was inhibited. From those phenomena, we suppose that Siglec-E is involved in the polarization of macrophage in sepsis. RAW264.7 cells and Siglec-E knock out mice were employed, and the models of sepsis were prepared by LPS and cecal ligation and puncture (CLP). Siglec-E RNA was interfered or over-expressed, then macrophage polarization was tested to confirm the role of Siglec-E. After that, JAK1-STAT6 inhibitors were used to verify the involvement of JAK1-STAT6 signal pathway. The purpose of this project is to elucidate that Siglec-E regulates the macrophage polarization in sepsis through JAK1-STAT6 signal pathway, which provides a new direction in the treatment of sepsis.

单核巨噬细胞极化是脓毒症免疫功能障碍的重要部分，但其分子机制尚不明确。Siglec-E多表达于单核巨噬细胞表面，我们前期研究显示，脓毒症小鼠巨噬细胞表面Siglec-E升高，且体内干扰Siglec-E后，脓毒症小鼠死亡率明显升高。我们推测Siglec-E参与脓毒症巨噬细胞的极化过程。课题采用RAW264.7细胞及Siglec-E基因敲除小鼠，以LPS及盲肠结扎穿孔术制备脓毒症模型，通过Siglec-E RNA干扰及过表达检测巨噬细胞极化指标来验证Siglec-E对巨噬细胞极化的作用；进一步采用JAK1-STAT6抑制剂来证实Siglec-E发挥作用受到JAK1-STAT6通路的调控。本课题旨在证实Siglec-E通过JAK1-STAT6通路调节脓毒症巨噬细胞M2极化，也证实JAK1-STAT6是Siglec-E发挥免疫调节的重要分子通路，为脓毒症治疗提供新方向。

脓毒症是指机体对感染的调节反应失控，从而引起的威胁生命的器官功能障碍。单核巨噬细胞通过表面的受体识别病原微生物并将其吞噬，而后经抗原呈递作用呈递给T淋巴细胞，并产生大量炎症细胞因子和趋化因子调节适应性免疫。巨噬细胞的极化类型比较繁杂，其中M1和M2是巨噬细胞的两个极化方向。Siglec-E表达于中性粒细胞及单核巨噬细胞表面，为主要的免疫炎症调控分子。我们研究发现：Siglec-E通过JAK1-STAT6 分子通路参与了脓毒症状态下巨噬细胞极化的调节过程，可以作为脓毒症治疗研究的一个新靶点，为脓毒症的防治提供新的思路。我们进一步开展了脓毒性心肌病的相关研究，证实脓毒症发生时心脏存在收缩及舒张功能障碍，并且心脏组织存在免疫细胞浸润的改变，可通过调节Siglec-E改变脓毒症心脏组织浸润免疫细胞的改变，从而改善脓毒性心肌损伤，改善脓毒症预后。