Modulation of glutamate metabolic reprogramming via Ras-Raf-MEK/ERK signaling alleviates immune inflammation of astrocytes in glaucomatous neurodegeneration

Normal-tension glaucoma (NTG) is characterized by chronic progressive retinal ganglion cell (RGCs) death with progressive optic nerve damage and a diminished visual field that is not accompanied by elevated intraocular pressure (IOP). Recently, the immunological mechanisms underlying nerve injury in glaucoma have been increasingly discussed. Astrocytes are important immune components of the retina that play a crucial role in regulating retinal plasticity and protecting neurons. Studies have revealed that astrocyte dysfunction triggers optic neuropathy without affecting IOP and could be a novel therapeutic target. Here, we constructed an experimental autoimmune glaucoma (EAG) model and used mass spectrometry techniques and metabolomics to detect metabolic changes in the retina. Furthermore, we performed in vitro and in vivo mechanistic analyses. Taken together, our findings indicate that regulating Ras-Raf-MEK/ERK signaling rescues glutamate-glutamine metabolism in astrocytes and protects RGCs against neuroinflammation damage. And we propose that Syngap1 is a potential target for the regulation of astrocyte metabolic reprogramming and the Ras signaling pathway. Our study provides novel insights into the immunopathogenesis related to glaucomatous neurodegeneration and a promising direction for the development of new therapies for neuropathy.

Astrocyte; Glaucoma; Glutamate-glutamine metabolism; Neuroimmune; Optic nerve degeneration; Ras-Raf-MEK/ERK signaling pathway.