TREM-2在脓毒症巨噬细胞M1/M2极化中的作用及分子机制

Immune dysfunction, one of the important pathogeneses of sepsis, is considered to be associated with macrophage polarization. Triggering receptor expressed on myeloid cells-2 (TREM-2), which is expressed on macrophages, microglia, osteoclasts, et al., plays a pivotal role in inflammatory response in sepsis through its regulation on macrophage activation. In our pilot studies, it was demonstrated that the expression levels of TREM-2 were associated with inflammatory cytokines of M2 macrophage in sepsis mice, such as IL-4, IL-10, et al. In vitro experiments showed that levels of pro-inflammatory cytokines were significantly reduced and levels of anti-inflammatory cytokines were increased after LPS stimulation in TREM-2 overexpressed macrophage. Therefore, we hypothesize that TREM-2 is involved in the macrophage polarization, and plays an important role in the initiation and development of immune dysfunction in sepsis. The present project will, at the systemic, cellular and molecular levels, investigate the impact of TREM-2 on macrophage polarization in sepsis, clarify the roles of TREM-2 modulated macrophage polarization, and further to explore the molecular mechanism how TREM-2 mediates macrophage polarization. Findings of the present study may help shed new light on the immune intervention of sepsis.

免疫功能紊乱是脓毒症的关键发病机制，巨噬细胞M1/M2极化在脓毒症免疫功能紊乱中发挥重要作用。研究报道髓系细胞促发受体-2（TREM-2）及其介导的信号通路通过调节巨噬细胞活性，参与脓毒症免疫炎症反应。我们前期研究发现脓毒症小鼠巨噬细胞TREM-2表达与IL-4、IL-10等M2型巨噬细胞炎症因子水平相关；LPS 刺激TREM-2高表达巨噬细胞，促炎因子释放减少，而抑炎因子释放增加。因此本课题推测TREM-2可能通过调控脓毒症巨噬细胞极化，调节机体免疫功能状态，介导脓毒症的发生发展。本项目拟从整体、细胞、分子水平，运用基因敲除动物模型、基因转染/siRNA等技术，观察TREM-2对脓毒症巨噬细胞M1/M2极化的影响及其与脓毒症发生发展的相关性，明确TREM-2调节巨噬细胞极化在脓毒症中的作用，深入探讨TREM-2调控巨噬细胞极化的分子机制，为探索脓毒症免疫调节治疗新策略供理论依据。

免疫功能紊乱是脓毒症的关键发病机制，巨噬细胞M1/M2 极化在脓毒症免疫功能紊乱中发挥重要作用。研究报道髓系细胞促发受体-2（TREM-2）及其介导的信号通路通过调节巨噬细胞活性，参与脓毒症免疫炎症反应。我们研究发现：1 TREM-2通过增加M2型炎症介质释放，提高巨噬细胞吞噬杀菌能力减轻脓毒症脏器损害，改善脓毒症生存率；2 过继回输TREM-2高表达巨噬细胞能明显改善盲肠结扎穿孔脓毒症小鼠感染和炎症反应严重程度、重要脏器的形态功能以及生存率；3进一步体外研究证实TREM-2可诱导巨噬细胞向M2型巨噬细胞分化，增加M2型细胞因子表达，抑制M1型细胞因子表达。本研究发现TREM-2在脓毒症发生发展中具有保护作用，并阐明其作用机制，从而为阐述脓毒症的发病机制、发现脓毒症防治的新的分子靶标提供理论依据。