TRB3介导脂肪组织巨噬细胞极化在2型糖尿病ApoE-/-/LDLR-/-小鼠易损斑块形成中的作用

Adipose tissue inflammation is an essential pathological process involved in diabetes and atherosclerotic vulnerable plaque formation. In diabetes, macrophages in adipose tissue shifting from M1 to M2 polarization，inflammation from which plays a major role during vulnerable plaque formation. Our previous studies demonstrated that M1-to-M2 ratio and TRB3 expression in adipose tissue were significantly increased in diabetic atherosclerosis mice; however，the regulating function of TRB3 on macrophage polarization and whether TRB3 could build the bridge between adipose tissue macrophage polarization in diabetes and atherosclerotic vulnerable plaque formation via TRB3/NF-κB signaling pathway remain unclear. In this study,we carry out the experiments in the levels of clinical patients,cells and animals, we developed an in vitro coculture system composed of adipocytes and macrophages and examined the effects of TRB3 gene overexpression and silencing on macrophage polarization and inflammatory factors. Then we discussed the effectiveness of fat transplantation and TRB3 gene silencing on NF-κB pathway, macrophage polarization and atherosclerotic plaque stability in diabetic ApoE-/-/LDLR-/- mice. Our findings can offer new ideas and therapeutic targets for early intervention of diabetic vulnerable plaque.

脂肪组织炎症是2型糖尿病和动脉粥样硬化易损斑块形成的共同根源，糖尿病状态下，脂肪组织巨噬细胞由M2型向促炎的M1型转化，其诱导的炎症是导致糖尿病易损斑块形成的重要环节。我们的前期工作显示，2型糖尿病动脉粥样硬化小鼠脂肪组织巨噬细胞M1/M2比值及TRB3表达均明显升高，但TRB3对巨噬细胞极化是否具有调控作用，能否通过对TRB3/NF-κB信号途径的调控，架起2型糖尿病脂肪组织巨噬细胞极化和易损斑块形成的桥梁尚不清楚。本课题拟在临床患者、细胞水平及整体动物水平，采用脂肪细胞和巨噬细胞共培养，探讨TRB3过表达或TRB3基因沉默对巨噬细胞极化和炎症因子的影响；以2型糖尿病ApoE-/-/LDLR-/-小鼠为研究对象，研究脂肪移植和TRB3基因沉默等干预措施对NF-κB信号途径和巨噬细胞极化的影响以及稳定2型糖尿病易损斑块的可行性。该研究结果可为糖尿病易损斑块的早期防治提供新的思路和靶点。

脂肪组织中巨噬细胞极化是造成糖尿病患者脂肪组织乃至全身慢性炎症状态的重要原因。但是糖尿病状态下脂肪组织巨噬细胞极化的机制涉及多种因素的协同作用，至今仍未阐明，因此缺乏有效的干预措施。本项目综合国内外研究现状，在深入分析糖尿病管周脂肪巨噬细胞极化的基础上，提出TRB3是调控糖尿病脂肪组织巨噬细胞炎症，参与动脉粥样硬化斑块形成关键信号通路的假说，并开展了相应的前期工作。本课题采用转化医学的研究模式，以TRB3管周脂肪巨噬细胞活化为切入点，在临床样本，细胞和整体水平上探讨TRB3在管周脂肪巨噬细胞极化的角色，验证TRB3沉默对脂肪炎症与动脉粥样硬化斑块的治疗作用。这些结果将为深入研究脂肪炎症与动脉粥样硬化的发生机制，探索新的有效治疗靶点，实现综合防治提供理论依据和实验基础。