电针通过神经元α7nAChR调控Treg减轻脑缺血后神经炎症的作用及其机制

Stroke is the leading cause of mortality in China. We firstly reported that electroacupuncture (EA) preconditioning on Baihui acupoint (GV20) could induce ischemic tolerance in brain. Granted by National Natural Science Foundation (No. 30873326), we observed that the neuroprotection of EA preconditioning was dependent on the up-regulation of alpha7 nicotinic acetylcholine receptor (α7nAChR) in neurons, and inhibited the post-ischemic neuroinflammation. However, the mechanisms of the EA-modulated neuroinflammation via α7nAChR are still to be elucidated. Regulatory T cells (Tregs) are major protective immunomodulators of cerebral ischemic injury. Furthermore, transforming growth factor-β1 (TGF-β1) plays a key role in the development and immunosuppressive function of Tregs. Our preliminary trials showed that EA restrained the Tregs decline in the early stage of cerebral ischemia/reperfusion, and the activation of α7nAChR increased the level of neuron-released TGF-β1. Therefore, it is indicated that the inhibition of the post-ischemic neuroinflammation by EA might be associated with the modulation in the development and immunosuppressive function of Tregs via α7nAChR, which indicated that α7nAChR seems to be a critical regulator for immunosuppressive function of Tregs. Based on the previous studies, we are going to further investigate the effects and mechanisms in EA-modulated development and functional status of Tregs via α7nAChR, which will not only provide the theoretical support for EA-induced neuroprotection, but also lead to novel targets for developing neuroprotective drugs via the modulation of neuroinflammtion.

脑卒中是我国第一位死因，我们率先报道电针刺激百会穴可诱导缺血耐受。在国科金资助下，我们发现电针上调神经元α7nAChR表达，抑制缺血再灌注后的神经炎症发挥脑保护作用。然而，电针如何通过α7nAchR调节神经炎症的机制尚不清楚。研究证实，Treg是脑缺血损伤的关键保护性免疫调节因素，TGF-β1是影响Treg分化和功能维持的关键调节因子。初步结果显示，电针可抑制脑缺血再灌注早期Treg减少，激活α7nAchR可促进神经元产生TGF-β1，提示电针可通过神经元α7nAChR调控Treg分化和功能抑制神经炎症，从而减轻脑缺血损伤。本项目拟在前期实验的基础上，利用α7nAChR基因敲除小鼠，采用功能、形态和分子生物学等综合方法，研究电针通过α7nAChR调控Treg分化和功能的作用及其分子机制，不仅为进一步阐明电针脑保护的作用提供新的理论依据，而且为研发调控神经炎症发挥脑保护药物提供新靶点。

电针能够显著改善脑缺血损伤后的神经功能，但其机制有待阐明。本项目采用功能、形态和分子生物学等综合方法，研究胆碱能抗炎通路中的关键分子α7nAChR在电针调控神经炎症治疗脑缺血损伤中的作用及其机制。我们的结果如下：1、电针预处理可以上调脑缺血再灌注后大鼠脑内神经元 α7nAChR 表达，上调CD4+CD25+Treg水平，增加神经元转化生长因子TGF-β1的分泌；上调神经元α7nAChR能够抑制NLRP3炎症小体的产生，减少炎症小体相关分子的表达，从而减轻大脑神经炎症反应，发挥脑保护作用；2、电针能够作用于小胶质细胞α7nAChR，促进小胶质细胞由促炎表型（M1型）向抗炎表型（M2型）转化，减少缺血半暗带内促炎症因子TNF-α的水平，增加抗炎症因子IL-10的水平，维持脑内炎症反应平衡，从而改善脑缺血损伤大鼠神经行为学预后。上述结果表明：电针能够作用于脑内不同类型细胞上的α7nAChR，通过不同途径影响不同细胞功能，使各类细胞向有益自身的方向转化，从而发挥神经保护作用。研究电针通过α7nAChR 调控神经炎症的作用及其分子机制，不仅为进一步阐明电针脑保护的作用提供新的理论依据，而且为研发调控神经炎症发挥脑保护作用的药物提供新靶点。