VEGFD/VEGFR3依赖IL-3/IL-3Rα信号途径介导缺血性脑卒中后星形胶质细胞与小胶质细胞间抗炎对话障碍

o investigatethe role of IL-3/IL-3Rαcross-talk dysfunction between astrocytes and microglia in microglial lipid metabolism reprogramming and lipid droplets accumulation as well as neuroinflammation in ischemic stroke, and the regulatory effects of VEGFD/VEGFR3 on IL-3/IL-3Rα. Methods: The in vivo transient middle cerebral artery occlusion (tMCAO) model was established in mice. The oxygen-glucose deprivation and reoxygenation (OGD/Re) model was established in vitro. Immunohistochemistry,Western Blotting, and ELISA were used to observe the effects of VEGFD/VEGFR3 activation on the transformation of pro-inflammatory astrocytes and microglia , and the protein levels of IL-3, IL-3Rα and pro-inflammatory factors. Lipid metabolites, carnitine palmitoyltransferase 1A (CPT1A) protein level, lipid accumulation and phagocytosis of OGD/Re-induced microglia were detected by metabolomics and immunofluorescence. The above indicators were observed after the administration of the VEGFR inhibitor axitinib or recombinant IL-3. Results: VEGFD/VEGFR3-mediated tMCAO or OGD/Re-induced decrease in both astrocytic IL-3 and microglial IL-3Rα levels, followed by downregulation of mitochondrial fatty acid oxidation rate-limiting enzyme CPT1A in microglia, causing lipid droplets accumulation, decrease in cellular membrane phospholipid levels, cellular membrane damage, pro-inflammatory response and phagocytic dysfunction, which can be reversed by recombinant IL-3 or axitinib. Conclusions: After ischemic stroke, VEGFD/VEGFR3 contributes to the dysfunction of astrocytic IL-3-microglial IL-3Rα cross-talk, leading to lipid metabolism reprogramming, accumulation of lipid droplets, and exacerbation of neuroinflammation in microglial. Recombinant IL-3 or axitinib may be potential drugs for the treatment of ischemic stroke.