Microglia suppress Müller cell FGF1 and contribute to retinal ganglion cell degeneration in glaucoma.

Glaucoma is a progressive neurodegenerative disease characterized by retinal ganglion cell (RGC) loss, in which glial activation and neuroinflammation contribute importantly to disease progression. However, the mechanisms by which microglia-Müller cell interactions influence retinal neuroinflammation and neurotrophic support during glaucoma remain unclear. Here, we aimed to identify glia-associated regulatory factors involved in microglia-Müller cell communication during glaucoma and to determine their contribution to retinal neurodegeneration. A chronic ocular hypertension (COH) mouse model and a conditioned medium (CM)-based inflammatory system were used to investigate microglia-Müller cell interactions and the role of fibroblast growth factor 1 (FGF1) in retinal neuroinflammation. Sustained intraocular pressure (IOP) elevation induced glial activation and progressive RGC degeneration in COH retinas. Transcriptomic profiling of Müller cells exposed to microglia-CM identified FGF1 as a significantly downregulated candidate neurotrophic factor, accompanied by enrichment of immune and inflammatory pathways. Functionally, Müller cell FGF1 deficiency exacerbated, whereas exogenous FGF1 attenuated, inflammation-induced RGC apoptosis in vitro. In vivo, intravitreal rFGF1 reduced RGC apoptosis, preserved RGC survival, and maintained retinal structure without affecting IOP. Consistently, reduced FGF1 expression was observed in Müller cell-enriched regions of human glaucomatous retinas. Together, these findings suggest that microglia-driven inflammation suppresses Müller cell FGF1 expression, thereby impairing neurotrophic support and increasing retinal vulnerability during COH. Restoration of FGF1 signaling confers neuroprotection independently of IOP reduction and may represent a promising glia-targeted therapeutic strategy for glaucoma.