GPR40 Attenuates Age-Related Macular Degeneration by Suppressing Retinal Microglial NLRP3 Inflammasome Activation Via ERK Signaling.

Retinal neuroinflammation is a key pathological feature of age-related macular degeneration (AMD), primarily driven by aberrant microglial cell activation. The expression and role of G-protein-coupled receptor 40 (GPR40), in AMD remain unclear. To investigate this pathology, we established a sodium iodate-induced mouse model of non-exudative AMD and performed in vitro experiments using LPS-stimulated microglial cells. The results showed that activation of the GPR40 receptor significantly promoted the polarization of microglial cells from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, effectively inhibiting neuroinflammation. Mechanistic studies revealed that GPR40 negatively regulates the ERK signaling pathway, inhibiting NLRP3 inflammasome activation and the release of pro-inflammatory cytokines such as IL-1β and TNF-α. In both in vivo and in vitro experiments, GPR40 activation protected photoreceptors by suppressing neuroinflammation caused by excessive microglial activation. In conclusion, this study reveals, for the first time, the critical role of GPR40 in regulating retinal neuroinflammation and its molecular mechanism. It highlights the potential therapeutic value of targeting the GPR40-ERK signaling axis to control the neuroinflammatory cascade and delay the progression of AMD and other retinal degenerative diseases.