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Theranostics 2021; 11(17):8480-8499. doi:10.7150/thno.60031 This issue Cite

Research Paper

Astrocytic YAP protects the optic nerve and retina in an experimental autoimmune encephalomyelitis model through TGF-β signaling

Qian Wu^1,2#, Xuemeng Miao^2#, Jingjing Zhang^5#, Ludan Xiang², Xiuchun Li⁴, Xiaomei Bao⁵, Siyu Du², Mianxian Wang⁵, Shuangda Miao⁴, Yiren Fan², Wei Wang², Xingxing Xu⁵, Xiya Shen⁵, Danlu Yang⁵, Xiwu Wang⁵, Yuanyuan Fang², Lixin Hu², Xuyi Pan⁴, Haoru Dong⁴, Hui Wang⁴, Ying Wang^3✉, Jia Li^4✉, Zhihui Huang^1,2,4✉

1. School of pharmacy and Holistic Integrative Pharmacy Institutes, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
2. School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
3. Phase I Clinical Research Center, Zhejiang Provincial People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310053, China.
4. The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
5. School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
^# These authors contribute equally: Qian Wu, Xuemeng Miao, Jingjing Zhang

✉ Corresponding authors: Ying Wang, Email: nancywangyingcom. Jia Li, Email: susannitacom. Zhihui Huang, Email: huang0069edu.cn.

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-β (TGF-β) pathway, and XMU-MP-1 which inhibits Hippo kinase MST1/2 to activate YAP.

Results: We found that YAP was significantly upregulated and activated in the astrocytes of optic nerve in EAE mice. Conditional knockout of YAP in astrocytes caused more severe inflammatory infiltration and demyelination in optic nerve, and damage of retinal ganglion cells (RGCs) in EAE mice. Moreover, YAP deletion in astrocytes promoted the activation of astrocytes and microglia, but inhibited the proliferation of astrocytes of optic nerve in EAE mice. Mechanically, TGF-β signaling pathway was significantly down-regulated after YAP deletion in astrocytes. Additionally, both qPCR and immunofluorescence assays confirmed the reduction of TGF-β signaling pathway in YAP^GFAP-CKO EAE mice. Interestingly, SRI-011381 partially rescued the deficits in optic nerve and retina of YAP^GFAP-CKO EAE mice. Finally, activation of YAP signaling by XMU-MP-1 relieved the neuroinflammation and demyelination in optic nerve of EAE mice.

Conclusions: These results suggest astrocytic YAP may prevent the neuroinflammatory infiltration and demyelination through upregulation of TGF-β signaling and provide targets for the development of therapeutic strategies tailored for MS-ON.

Keywords: optic neuritis, astrocytes, YAP, TGF-β1, neuroinflammation

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