Abstract
PURPOSE: Optic neuropathy is a leading cause of blindness. Autophagy activation has been reported following optic nerve injury, but its precise role remains unclear. We investigated the involvement of autophagy in the early stages of optic nerve injury and explored potential therapeutic strategies.
METHODS: A mouse optic nerve crush (ONC) model was established. Autophagy levels were assessed at different time points using electron microscopy and markers LC3 and Beclin-1. The relationship between autophagy and cell death was examined by Beclin-1 co-localization combined with TUNEL. Receptor-interacting protein (RIP3) knockout mice were used to determine its regulatory role in microglial autophagy-related cell death. Finally, the neuroprotective effect of inhibiting this pathway was evaluated with pharmacological inhibitors.
RESULTS: A peak in autophagy activation was observed 1 day after optic nerve injury. Beclin-1 was expressed across various cell populations, including retinal ganglion cells (RGCs), microglia, and astrocytes. Excessive autophagy activation induced cell death specifically in microglia, not in RGCs or astrocytes. Knockout of RIP3 significantly reduced microglial autophagy-related cell death and attenuated retinal neuroinflammation. Moreover, intravitreal administration of the RIP3 inhibitor GSK-872 or the autophagy inhibitor 3-MA reduced RGC death and improved visual function.
CONCLUSIONS: Autophagy-related cell death represents a novel mechanism of microglial activity. Targeting RIP3-mediated autophagy may provide a promising strategy for early intervention in optic neuropathies.