Article

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

Shuai Wang1,2, Yi Guo1, Rui-qi Cao1, Yong-ming Zhu1, Shi-gang Qiao3, Hua-ping Du4, Yuan Liu4, Yuan Xu4, Xian-yong Zhou1, Lei Sun3, Qi-xia Lu3, Ingmar Schoen2, Hui-ling Zhang1
1 Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China
2 Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland RCSI, Dublin, Ireland
3 Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University, Kunshan 215000, China
4 Department of Neurology, Suzhou Ninth People’s Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Soochow University, Suzhou 215200, China
Correspondence to: Hui-ling Zhang: zhanghuiling@suda.edu.cn,
DOI: 10.1038/s41401-024-01405-6
Received: 16 February 2024
Accepted: 1 October 2024
Advance online: 30 October 2024

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 60 min 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.
Keywords: ischemic stroke; IL-3/IL-3Rα cross talk; VEGFD/VEGFR3; astrocytes; microglia; neuroinflammation

Article Options

Download Citation

Cited times in Scopus