PM2.5 exposure and retinal neurovascular dysfunction: Clinical and mechanistic evidence for complement C3/C3aR pathway involvement.

PM2.5 is a pervasive environmental toxicant associated with retinal neurodegeneration, yet the mechanisms remain unclear. This study combined clinical, animal, and cellular approaches to investigate whether C3/C3aR signaling mediates PM2.5‑induced retinal neurovascular damage. In retrospective longitudinal glaucoma cohort, a linear mixed‑effects model analyzed PM2.5 effects on inflammatory markers. In mice, we examined PM2.5 effects on retinal complement, microglia activation, neurovascular function, and vision. The protective effect of the C3aR blocker SB290157 was also evaluated. BV2 and retinal endothelial cells were used to study C3‑dependent microglial polarization and its vasoregulatory effects. In clinical experiment, we identified a significant association between short-term PM2.5 exposure and systemic complement dysregulation, characterized by a decrease in serum C3c. In mice, PM2.5 exposure induced marked retinal C3 activation. This change was characterized by microglial activation, vascular dysfunction, and retinal structural and functional impairment. In vitro, PM2.5 directly induced C3/C3aR-dependent microglial M1 polarization and stimulated endothelial vasoconstrictor secretion via microglial crosstalk. Treatment with C3aR inhibitor attenuated the vicious cycle, preserving retinal structure and visual function. In conclusion, C3/C3aR axis serves as a key mechanistic link between PM2.5 exposure and retinal neurodegeneration. Targeting this pathway may offer a therapeutic strategy for mitigating pollution-related retinal damage.