ω-3PUFAs Inhibit Hypoxia-Induced Retinal Neovascularization via Regulating Microglial Pyroptosis through METTL14-Mediated m6A Modification of IFNB1 mRNA.

Retinal neovascular disease is the leading reason of vision impairment in all ages. Here, we figured out the function and mechanism of omega-3 polyunsaturated fatty acids (ω-3PUFAs) in hypoxia-induced retinal neovascularization by focusing on microglial pyroptosis. Microglia BV-2 cells were given ω-3PUFAs treatment and co-cultured with mouse retinal microvascular endothelial cells (MRMECs) under hypoxia. Tube formation assay, transwell assay and wound healing assay were utilized to monitor the MRMEC angiogenesis. Cell counting kit-8, western blot, lactate dehydrogenase assay, and enzyme-linked immunosorbent assay were used to assess pyroptosis of BV-2 cells. RNA sequencing and methylated RNA immunoprecipitation-polymerase chain reaction were utilized to identify the target gene of methyltransferase-like 14 (METTL14) and its N6-methyladenosine (m6A) level in BV-2 cells. BV-2 cells prominently enhanced MRMEC angiogenesis under hypoxia, but this effect was abolished after ω-3PUFAs treatment. ω-3PUFAs inhibited pyroptosis in hypoxia-induced BV-2 cells, and BV-2 cell pyroptosis boosted angiogenesis of MRMECs. Additionally, ω-3PUFAs markedly augment the expression of MELLL14 in BV-2 cells, and METTL14 knockdown promoted BV-2 cell pyroptosis and BV-2 cell-mediated angiogenesis in MEMECs. Mechanistically, interferon beta 1 (IFNB1) was a target of METTL14, and METTL14 silencing increased the mRNA expression and decreased the m6A modification of IFNB1 in BV-2 cells. Our results uncovered that ω-3PUFAs diminished hypoxia-induced retinal neovascularization through controlling microglial pyroptosis via METTL14-mediated m6A modification. This study offers a novel potential target for the treatment of retinal neovascular diseases. [ABSTRACT FROM AUTHOR]

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