外泌体/miR-155/PD-L1轴在LAP+树突状细胞调控动脉粥样硬化中的作用和机制研究

Immune and inflammatory response participate in the pathological process of atherosclerosis (AS), dendritic cells (DCs) can affect the process of AS via regulate the immune and inflammatory response. Our previous study confirmed that the latency-associated-peptide (LAP)+CD4+ T cells prevented AS and the number and function of LAP+CD11c+ DCs was defective in atherosclerotic mice. Preliminary experiments demonstrated that the adoptive transfer of LAP+CD11c+ DCs could significantly inhibit the development of atherosclerotic plaque, the exosomes of LAP+CD11c+ DCs (DexLAP+) with a low expression of miR-155 and a high expression of programmed death ligand 1 (PD-L1), and DexLAP+ can reshape the immune balance.. Accordingly, we assume that: LAP+CD11c+ DCs regulate immune and inflammatory response and the development of AS through DexLAP+. To test this hypothesis, in atherosclerotic mice, we explore to whether the LAP+CD11c+ DCs regulate immune and inflammatory response via DexLAP+/miR-155/PD-L1/Regulatory T cells (Tregs)/ Effector T cells axis, and inhibit the development of atherosclerotic plaque, ultimately, provide a new target for preventing and treating AS base on LAP+CD11c+ DCs.

免疫炎症反应贯穿动脉粥样硬化病变的始终，树突状细胞能通过调节免疫炎症反应影响动脉粥样硬化进程。我们前期证实了潜伏相关肽（LAP）+淋巴细胞在动脉粥样硬化中的保护作用以及LAP+树突状细胞数量和功能缺损。预实验表明，过继转输LAP+树突状细胞可显著抑制动脉粥样硬化斑块形成，LAP+树突状细胞外泌体低表达miR-155和高表达程序性死亡配体1（PD-L1），进一步发现过继转输此外泌体能够重塑免疫平衡。据此，我们假设：LAP+树突状细胞通过外泌体调控免疫炎症反应及动脉粥样硬化。拟建立动脉粥样硬化模型，阐明LAP+树突状细胞通过外泌体/miR-155/PD-L1/淋巴细胞轴调控免疫炎症反应，继而影响动脉粥样硬化斑块形成，提出以LAP+树突状细胞为靶点防治动脉粥样硬化的新策略。

免疫炎症反应贯穿动脉粥样硬化病变的始终，树突状细胞能通过调节免疫炎症反应影响动 脉粥样硬化进程。我们前期证实了潜伏相关肽（LAP）+淋巴细胞在动脉粥样硬化中的保护作用以及LAP+树突状细胞数量和功能缺损。实验表明，过继转输LAP+树突状细胞可显著抑制动脉粥样硬化斑块形成，LAP+树突状细胞可以减少ApoE-/-小鼠免疫器官内Th1和Th17比例，增加Treg和 M2巨噬细胞比例，减少动脉粥样硬化斑块严重程度。并且LAP+树突状细胞与T细胞共培养后体外抑制CD4+T细胞增殖及诱导分化。进一步发现关键分子胰岛素样生长调节因子-1（IGF1）在LAP+树突状细胞中显著增加，且IGF1能够诱导DC耐受，并且能够减轻DC的炎症水平。据此，我们假设：LAP+树突状细胞通过IGF1调控免疫炎症反应及动脉粥样硬化，继而影响动脉粥样硬化斑块形成， 提出以LAP+树突状细胞为靶点防治动脉粥样硬化的新策略。