GABA/GABA-A受体通路调控树突状细胞的免疫功能抑制apoE-/-小鼠腹主动脉瘤形成的机制

Abdominal aortic aneurysm (AAA) and its associated arterial rupture is a deadly vascular and inflammatory disease. How to prevent the inflammatory cells from being too active and the degradation of extracellular matrix is still a clinical problem unresolved. Dendritic cell (DC), as antigen presenting cells initiating immune responses in vivo, its maturation and function plays an critical role in the pathogenesis of AAA. In recent years, it has been found that the inhibitory neurotransmitter of the central nervous system, γ-aminobutyric acid (GABA) - type A receptor, play an important role in the regulation of inflammatory immune cells and been involved in the pathological processes of certain autoimmune diseases. Our previous work showed that GABA inhibited the formation of AAA by stimulating GABA-A receptors and infiltration of DCs and Th1 cells in damaged vessel. Furthermore, the primary experiments found that there are functional GABA-A receptors on the surface of DCs in AAA mice. On this basis, we would further investigate how to GABA/GABA-A pathway slow down the rate of migration of immature DCs to ECM , weaken its ability to degrade ECM and how to inhibit the antigen presentation function of mature DCs. We hope to be able to discover the possible principles of GABA/GABA-A receptor pathway attenuate the formation of abdominal aortic aneurysm by regulating the immune function of dendritic cells in apoE-/- mice.

腹主动脉瘤(AAA)及其并发的动脉破裂是一类致命的血管炎症性疾病。如何抑制炎症细胞的活化，阻止血管细胞外基质(ECM)的降解是目前AAA治疗中尚未解决的难题。树突状细胞(DCs)作为体内抗原呈递细胞和炎症免疫反应启动者，其成熟状态和功能变化在AAA的发病中起着重要作用。近年发现，抑制性神经递质γ-氨基丁酸(GABA)A 型受体能够调控多种炎症免疫细胞的功能，参与某些自身免疫性疾病的病理过程。我们的前期工作发现，GABA通过激活GABA-A受体可抑制AAA形成，减少病变局部DCs和Th1细胞的浸润。初步实验表明，AAA模型小鼠DCs表面存在着功能性的GABA-A受体。本项目拟研究GABA/GABA-A通路如何减慢未成熟DCs向ECM迁移的速度和削弱其对ECM降解的能力，以及如何抑制成熟DCs的抗原呈递功能，从而揭示GABA/GABA-A受体通路调控树突状细胞的免疫功能抑制AAA形成的机制。

腹主动脉瘤（abdominal aortic aneurysm, AAA）及其并发的动脉破裂是一类致命的血管性疾病，动脉粥样硬化（atherosclerosis, AS）是其常见的病因。AAA的主要病理改变为炎症细胞浸润，血管平滑肌细胞凋亡，弹力纤维和胶原纤维断裂，细胞外基质（extracellular matrix, ECM）降解，从而导致动脉管腔扩张或膨出甚至发生破裂，造成严重出血，危及生命。因此，如何抑制炎症细胞的活化，阻止ECM降解是预防AAA的主要措施，也是目前尚未解决的临床难题。课题组通过细胞和动物实验研究发现，未成熟DCs细胞膜表面GABA-A受体激活后，GABA-A受体 α5发生内化，内化的 α5与ERM家族根蛋白肌球蛋白形成复合物，通过p38MAPK信号通路，使骨架结合蛋白根蛋白去磷酸化，肌动蛋白解离速度下降，伪足伸出受阻，DCs延缓进入ECM；同时，GABA-A受体 α5发生磷酸化/去磷酸化，调控MAPK信号p38通路，抑制MMPs的分泌，减轻ECM的降解。另一方面，成熟DCs细胞膜表面GABA-A受体激活后，抑制其抗原呈递功能，减轻T淋巴细胞的活化。进而证明GABA激动GABA-A受体后，抑制成熟DCs的抗原呈递功能；证明GABA激动GABA-A受体后，削弱未成熟DCs的迁移及分泌MMPs的能力，减轻对ECM的降解。课题组通过研究GABA/GABA-A受体通路对于AAA中DCs免疫功能的调控作用，力求为AS相关性AAA的治疗提供一个新的防治靶点。