苏州大学张慧灵课题组发现，VEGFD/VEGFR3信号通路促成星形胶质细胞IL-3/小胶质细胞IL-3Rα的交互功能障碍，并推动小鼠缺血性中风中的神经炎症。这一研究成果于2024年10月30日在线发表在国际学术期刊《中国药理学报》上。

研究人员探讨了IL-3/IL-3Rα交互及其调控机制在缺血性中风中的作用。通过对右侧大脑中动脉（MCA）进行60分钟的腔内阻塞后再灌注（I/R），在小鼠中诱导缺血性中风。使用经历缺氧-葡萄糖剥夺和再氧合（OGD/Re）的人工星形胶质细胞或小胶质细胞作为脑缺血的体外模型，研究人员发现I/R和OGD/Re均显著诱导星形胶质细胞IL-3和小胶质细胞IL-3Rα蛋白水平的下降，同时伴随A1型星形胶质细胞和M1型小胶质细胞的促炎激活。

重要的是，星形胶质细胞来源的VEGFD作用于星形胶质细胞和小胶质细胞的VEGFR3，导致交互功能障碍和两种胶质细胞的促炎激活，从而介导神经细胞损伤。通过代谢组学和多种生化方法，研究人员证明了向小胶质细胞补充IL-3逆转了OGD/Re诱导的脂质代谢重编程，这通过CPT1A（线粒体β-氧化的限速酶）表达上调和甘油磷脂水平升高得到证实，导致脂滴积累减少，从而减少促炎激活和坏死，并增加小胶质细胞的吞噬功能。

值得注意的是，外源性IL-3和VEGFR拮抗剂阿西替尼重新建立了IL-3/IL-3Rα的交互，提高了小胶质细胞的脂质代谢水平。通过上调CPT1A恢复小胶质细胞的吞噬功能，减轻小胶质细胞的促炎激活，最终有助于大脑从I/R损伤中恢复。这些结果表明，VEGFD/VEGFR3信号通路促成了星形胶质细胞IL-3/小胶质细胞IL-3Rα交互的功能障碍，并驱动促炎激活，导致小胶质细胞的脂质代谢重编程。这些见解表明，VEGFR3拮抗或恢复IL-3水平可能是缺血性中风的潜在治疗策略。

研究人员表示，星形胶质细胞来源的IL-3激活小胶质细胞中的相应受体IL-3Rα。星形胶质细胞与小胶质细胞之间的这种交互改善了小鼠阿尔茨海默病的病理。

附：英文原文

Title: VEGFD/VEGFR3 signaling contributes to the dysfunction of the astrocyte IL-3/microglia IL-3Rα cross-talk and drives neuroinflammation in mouse ischemic stroke

Author: Wang, Shuai, Guo, Yi, Cao, Rui-qi, Zhu, Yong-ming, Qiao, Shi-gang, Du, Hua-ping, Liu, Yuan, Xu, Yuan, Zhou, Xian-yong, Sun, Lei, Lu, Qi-xia, Schoen, Ingmar, Zhang, Hui-ling

Issue&Volume: 2024-10-30

Abstract: Astrocyte-derived IL-3 activates the corresponding receptor IL-3Rα in microglia. This cross-talk between astrocytes and microglia ameliorates the pathology of Alzheimer’s disease in mice. In this study we investigated the role of IL-3/IL-3Rα cross-talk and its regulatory mechanisms in ischemic stroke. Ischemic stroke was induced in mice by intraluminal occlusion of the right middle cerebral artery (MCA) for 60min followed by reperfusion (I/R). Human astrocytes or microglia subjected to oxygen-glucose deprivation and reoxygenation (OGD/Re) were used as in vitro models of brain ischemia. We showed that both I/R and OGD/Re significantly induced decreases in astrocytic IL-3 and microglial IL-3Rα protein levels, accompanied by pro-inflammatory activation of A1-type astrocytes and M1-type microglia. Importantly, astrocyte-derived VEGFD acting on VEGFR3 of astrocytes and microglia contributed to the cross-talk dysfunction and pro-inflammatory activation of the two glial cells, thereby mediating neuronal cell damage. By using metabolomics and multiple biochemical approaches, we demonstrated that IL-3 supplementation to microglia reversed OGD/Re-induced lipid metabolic reprogramming evidenced by upregulated expression of CPT1A, a rate-limiting enzyme for the mitochondrial β-oxidation, and increased levels of glycerophospholipids, the major components of cellular membranes, causing reduced accumulation of lipid droplets, thus reduced pro-inflammatory activation and necrosis, as well as increased phagocytosis of microglia. Notably, exogenous IL-3 and the VEGFR antagonist axitinib reestablished the cross-talk of IL-3/IL-3Rα, improving microglial lipid metabolic levels via upregulation of CPT1A, restoring microglial phagocytotic function and attenuating microglial pro-inflammatory activation, ultimately contributing to brain recovery from I/R insult. Our results demonstrate that VEGFD/VEGFR3 signaling contributes to the dysfunction of the astrocyte IL-3/microglia IL-3Rα cross-talk and drives pro-inflammatory activation, causing lipid metabolic reprogramming of microglia. These insights suggest VEGFR3 antagonism or restoring IL-3 levels as a potential therapeutic strategy for ischemic stroke.

DOI: 10.1038/s41401-024-01405-6

Source: https://www.nature.com/articles/s41401-024-01405-6