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

作者：Wang, Shun; Zhang, Jing; Chen, Jun; Tang, Lanlan; Ke, Min; Xue, Yanni; He, Ying; Gong, Yan^*; Li, Zhi^*

来源：Applied Biochemistry and Biotechnology - Part A Enzyme Engineering and Biotechnology, 2024.

DOI：10.1007/s12010-023-04795-1

• omega-3PUFAs
• Retinal Neovascularization
• Microglia
• Pyroptosis
• m6A Modification

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 (omega-3PUFAs) in hypoxia-induced retinal neovascularization by focusing on microglial pyroptosis. Microglia BV-2 cells were given omega-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 omega-3PUFAs treatment. omega-3PUFAs inhibited pyroptosis in hypoxia-induced BV-2 cells, and BV-2 cell pyroptosis boosted angiogenesis of MRMECs. Additionally, omega-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 omega-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.

• 单位
  武汉大学; y