脂氧素促进小胶质细胞M2型极化减轻脑缺血损伤的研究

Inflammatory response following the cerebral ischemia accelerates the neuronal injury. So, we suggested a novel idea for the intervention of ischemic stroke is pro-resolution of inflammation following cerebral ischemia. With the support from National Natural Science Foundation of China, we investigated effects of lipoxins, pro-resolution lipid mediators, on the ischemic stroke. And found that neuronal injury induced by cerebral ischemia is attenuated by lipoxins. The mechanism of these phenomenons is the inhibitory effects of lipoxins on the microglial M1 polarization. Further research suggested that lipoxins may promote the microglial M2 polarization. As we known, M2 microglia has a potential for anti-inflammation, pro-resolution, phagocytosis. According to these findings, we hypothesize that lipoxins promotes microglial M2 polarization results in amelioration of cerebral ischemia. So, we will test this hypothesis in the present proposal. Aim 1, we will observe the relation between the effect of lipoxins on the microglial M1 phenotype and neuronal injury triggered by ischemic stroke. Aim 2, whether lipoxins promote the microglial phagocytosis results in attenuation of neurological dysfunction. Aim3, we will investigate the mechanism of microglial M2 polarization enhanced by lipoxins. In summary, the finding of present proposal will provide clear evidence for use of lipoxins for the treatment of ischemic stroke.

脑缺血后的炎症反应加剧了脑缺血所致的神经元损伤，为此，我们提出"促进炎症消退治疗脑缺血"的新思路。在国家自然科学基金资助下开展研究，应用促炎症消退介质脂氧素干预缺血性脑卒中模型取得了显著效果，部分机制在于脂氧素抑制M1型小胶质细胞的促炎作用及其相关信号通路。后续研究提示，脂氧素可以促进小胶质细胞向M2型极化。而M2型小胶质细胞具有抗炎促消退、促进吞噬死亡神经元的作用。因此，提出研究假设：脂氧素通过促进小胶质细胞向M2型极化，减轻脑缺血所致的神经损伤。本项目将首先研究脂氧素对小胶质细胞M1、M2表型的影响与脑缺血所致损伤的关系。其次，研究脂氧素调控小胶质细胞吞噬功能与脑缺血所致神经损伤的关系。最后，探讨脂氧素促进M2型小胶质细胞极化的可能机制。总之，本项目将明确脂氧素促进小胶质细胞向M2型极化减轻脑缺血损伤的作用，为脂氧素用于缺血性脑卒中的治疗提供研究依据和理论基础。

背景：脑缺血后的炎症反应加剧了脑缺血所致的神经元损伤。脂氧素可以促进小胶质细胞向 M2 型极化，而M2 型小胶质细胞具有抗炎促消退、促进吞噬死亡神经元的作用。因此，我们假设脂氧素通过促进小胶质细胞向 M2 型极化，促进小胶质细胞吞噬，减轻脑缺血所致的神经损伤。..研究内容：本项目将首先研究脂氧素对小胶质细胞 M1、M2 表型的影响，其次，研究脂氧素与吞噬与自噬的关系，最后，探究脂氧素作用于小胶质细胞与脑缺血所致损伤的关系。本项目将明确脂氧素作用于小胶质细胞对减轻脑缺血损伤的作用，为脂氧素用于缺血性脑卒中的治疗提供研究依据和理论基础。..结果和关键数据：实验表明脂氧素可经STAT6信号通路及PPARγ信号通路诱导小胶质细胞M2型转化，可通过上调表面 CD36 受体的表达而实现对小胶质细胞吞噬功能的促进作用，可促进小胶质细胞非mTOR依赖型自噬，并可减轻脑缺血损伤。..科学意义：脂氧素可通过促进小胶质细胞表型转化，增强其吞噬及自噬减轻脑缺血损伤，有助于深入了解小胶质细胞在缺血性神经损伤中所扮演的角色，为脑缺血的治疗奠定了基础。