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

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.

miR-216b-5p Inhibited the Progression of Experimental Optic Neuritis via Downregulating FAS

“…Optic nerve is the main transmission pathway of visual information. ON damage can be caused by craniocerebral injury, inflammation, high intraocular pressure, and tumor growth [ 1 ]. ON is also a common optic neuropathy.…”

“…Optic neuritis (ON) refers to various inflammatory lesions of the optic nerve, which is a more common optic nerve disease in young people [ 1 ]. According to the etiology, it can be divided into idiopathic optic neuritis, infectious and infection-related optic neuritis, autoimmune optic neuritis, and other optic neuritis that cannot be classified [ 2 ].…”

Emerging roles of the Hippo signaling pathway in modulating immune response and inflammation‐driven tissue repair and remodeling

“…Activation of YAP by XMU‐MP‐1, a pharmacological inhibitor of MST1/2, induced the expression of HMGCS1 in astrocytes, inhibited demyelination and neuroinflammation, and enhanced the functional recovery in EAE mice [124]. A similar role of YAP has been explored in optic neuritis, another crucial feature in multiple sclerosis [125]. Activated YAP in astrocytes of optic nerve prevents demyelination and neuroinflammation in EAE mice through TGF‐β pathways.…”

“…Conditional deletion of YAP in astrocytes exacerbated inflammatory microglia infiltration and demyelination process (Fig. 6), which was associated with the loss of retinal ganglion cells in EAE mice [125].…”

Astrocytic YAP prevents the demyelination through promoting expression of cholesterol synthesis genes in experimental autoimmune encephalomyelitis

“…Recent reports have shown that YAP is upregulated and activated in astrocytes through suppression of the Hippo pathway after spinal cord injury, and promotes glial scar formation and neural regeneration, and improves functional recovery of mice after SCI [ 41 ]. Also, our recent research has shown that astrocytic YAP could prevent the demyelination and neuroinflammation of the retina and optic nerve of EAE through upregulating TGF-β signaling [ 53 ]. Interestingly, consistent with these previous studies, present studies showed that in EAE mice, YAP was also upregulated and activated through suppression of Hippo pathway in astrocytes, not in microglia or neurons of spinal cords (Fig.…”