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

Xin Tan1,2,3, Jianshu Kang1,2, Hongkun Zhao1,2

  • 1Department of Ophthalmology, Yunnan Eye Institute & Key Laboratory of Yunnan Province, Yunnan Eye Disease Clinical Medical Center, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, China.

Inflammation
|January 6, 2026
PubMed

Insights

G-protein-coupled receptor 40 (GPR40) activation shifts microglial cells to an anti-inflammatory state, protecting retinal cells. Targeting the GPR40-ERK pathway may treat age-related macular degeneration (AMD) and other retinal diseases.

Area of Science:

  • Ophthalmology
  • Neuroscience
  • Immunology

Background:

  • Retinal neuroinflammation, driven by microglial activation, is central to age-related macular degeneration (AMD).
  • The role of G-protein-coupled receptor 40 (GPR40) in AMD pathogenesis is currently unknown.

Purpose of the Study:

  • To investigate the role and mechanism of GPR40 in regulating retinal neuroinflammation in AMD.

Main Methods:

  • Established a sodium iodate-induced mouse model of non-exudative AMD.
  • Utilized in vitro experiments with lipopolysaccharide (LPS)-stimulated microglial cells.
  • Analyzed GPR40's effect on microglial polarization, ERK signaling, NLRP3 inflammasome activation, and cytokine release.

Main Results:

  • GPR40 activation promoted M2 anti-inflammatory microglial polarization, suppressing neuroinflammation.
  • GPR40 negatively regulated the ERK signaling pathway, inhibiting NLRP3 inflammasome activation and pro-inflammatory cytokine release (IL-1β, TNF-α).
  • GPR40 activation protected photoreceptors from neuroinflammation in vivo and in vitro.

Conclusions:

  • GPR40 plays a critical role in modulating retinal neuroinflammation via the GPR40-ERK signaling axis.
  • Targeting GPR40 offers a potential therapeutic strategy for AMD and other retinal degenerative diseases.
Keywords:
Age-related macular degenerationCaspase-1ERK pathwayGPR40MicrogliaNLRP3Photoreceptors

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