Astrocytic YAP protects the optic nerve and retina in an experimental autoimmune encephalomyelitis model through TGF-β signaling
Qian Wu, Xuemeng Miao, Jingjing Zhang, Ludan Xiang, Xiuchun Li, Xiaomei Bao, Siyu Du, Mianxian Wang, Shuangda Miao, Yiren Fan, Wei Wang, Xingxing Xu, Xiya Shen, Danlu Yang, Xiwu Wang, Yuanyuan Fang, Li‐Xin Hu, Xuyi Pan, Haoru Dong, Hui Wang, Ying Wang, Jia Li, Zhihui Huang
Abstract
Rationale: Optic neuritis is one of main symptoms in multiple sclerosis (MS) that causes visual disability. Astrocytes are pivotal regulators of neuroinflammation in MS, and astrocytic yes-associated protein (YAP) plays a critical role in neuroinflammation. Meanwhile, YAP signaling is involved in visual impairment, including glaucoma, retinal choroidal atrophy and retinal detachment. However, the roles and underlying mechanisms of astrocytic YAP in neuroinflammation and demyelination of MS-related optic neuritis (MS-ON) remains unclear. Methods: To assess the functions of YAP in MS-ON, experimental autoimmune encephalomyelitis (EAE, a common model of MS) was established, and mice that conditional knockout (CKO) of YAP in astrocytes, YAP GFAP -CKO mice, were successfully generated. Behavior tests, immunostaining, Nissl staining, Hematoxylin-Eosin (HE) staining, TUNEL staining, Luxol Fast Blue (LFB) staining, electron microscopy (EM), quantitative real-time PCR (qPCR), gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) by RNA sequencing were used to examine the function and mechanism of YAP signaling based on these YAP GFAP -CKO mice and EAE model mice. To further explore the potential treatment of YAP signaling in EAE, EAE mice were treated with various drugs, including SRI-011381 that is an agonist of transforming growth factor- (TGF-) pathway, and XMU-MP-1 which inhibits Hippo kinase MST1/2 to activate YAP.