Free Fatty Acid Receptor 4 Activation Protects Against Choroidal Neovascularization in Mice

Abstract

Purpose : To examine whether free fatty acid receptor 4 (FFAR4) activation can protect against choroidal neovascularization (CNV), which is a common cause of blindness, and to elucidate the mechanism underlying the inhibition, we used the mouse model of laser-induced CNV to mimic angiogenic aspects of age-related macular degeneration (AMD).

Methods : Laser-induced CNV was compared between groups treated with an FFAR4 agonist or vehicle, and between FFAR4 wild-type (FFAR4^+/+) and knock out (FFAR4^-/-) mice on a C57BL/6J/6N background. The ex vivo choroid sprouting assay, including primary retinal pigment epithelium (RPE) and choroid, without retina was used to investigate whether FFAR4 affects choroidal angiogenesis. Western blotting for pNF-κB / NF-κB and qRT-PCR for Il-6, Il-1β, Tnf-α were used to examine the influence of FFAR4 on inflammation, known to influence CNV. RPE isolated from FFAR4^+/+ and FFAR4^-/- mice were used to assess RPE contribution to inflammation.

Results : The FFAR4 agonist suppressed laser-induced CNV in C57BL/6J mice, and CNV increased in FFAR4^-/- compared to FFAR4^+/+ mice. We showed that the FFAR4 agonist acted through the FFAR4 receptor. The FFAR4 agonist suppressed mRNA expression of inflammation markers (Il-6, Il-1β) via the NF-κB pathway in the retina, choroid, RPE complex. The FFAR4 agonist suppressed neovascularization in the choroid-sprouting ex vivo assay and FFAR4 deficiency exacerbated sprouting. Inflammation markers were increased in primary RPE cells of FFAR4^-/- mice compared with FFAR4^+/+ RPE.

Conclusions : In this mouse model, the FFAR4 agonist suppressed CNV, suggesting FFAR4 to be a new molecular target to reduce pathological angiogenesis in CNV.

This is a 2020 ARVO Annual Meeting abstract.