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FTO-mediated m6A modification alleviates autoimmune uveitis by regulating microglia phenotypes via the GPC4/TLR4/NF-κB signaling axis
Genes & Diseases ( IF 6.9 ) Pub Date : 2022-10-04 , DOI: 10.1016/j.gendis.2022.09.008
Siyuan He 1, 2, 3, 4 , Wanqian Li 1, 2, 3, 4 , Guoqing Wang 1, 2, 3, 4 , Xiaotang Wang 1, 2, 3, 4 , Wei Fan 1, 2, 3, 4 , Zhi Zhang 1, 2, 3, 4 , Na Li 5 , Shengping Hou 1, 2, 3, 4
Affiliation  

Uveitis, a vision-threatening inflammatory disease worldwide, is closely related to resident microglia. Retinal microglia are the main immune effector cells with strong plasticity, but their role in uveitis remains unclear. N6-methyladenosine (m6A) modification has been proven to be involved in the immune response. Therefore, we in this work aimed to identify the potentially crucial m6A regulators of microglia in uveitis. Through the single-cell sequencing (scRNA-seq) analysis and experimental verification, we found a significant decrease in the expression of fat mass and obesity-associated protein (FTO) in retinal microglia of uveitis mice and human microglia clone 3 (HMC3) cells with inflammation. Additionally, FTO knockdown was found to aggravate the secretion of inflammatory factors and the mobility/chemotaxis of microglia. Mechanistically, the RNA-seq data and rescue experiments showed that glypican 4 (GPC4) was the target of FTO, which regulated microglial inflammation mediated by the TLR4/NF-κB pathway. Moreover, RNA stability assays indicated that GPC4 upregulation was mainly regulated by the downregulation of the m6A “reader” YTH domain family protein 3 (YTHDF3). Finally, the FTO inhibitor FB23-2 further exacerbated experimental autoimmune uveitis (EAU) inflammation by promoting the GPC4/TLR4/NF-κB signaling axis, and this could be attenuated by the TLR4 inhibitor TAK-242. Collectively, a decreased FTO could facilitate microglial inflammation in EAU, suggesting that the restoration or activation of FTO function may be a potential therapeutic strategy for uveitis.



中文翻译:

FTO 介导的 m6A 修饰通过 GPC4/TLR4/NF-κB 信号轴调节小胶质细胞表型减轻自身免疫性葡萄膜炎

葡萄膜炎是一种世界范围内威胁视力的炎症性疾病,与常驻小胶质细胞密切相关。视网膜小胶质细胞是主要的免疫效应细胞,可塑性强,但其在葡萄膜炎中的作用尚不清楚。N6-甲基腺苷(m 6 A)修饰已被证明参与免疫反应。因此,我们在这项工作中旨在确定葡萄膜炎中小胶质细胞的潜在关键 m 6 A 调节因子。通过单细胞测序(scRNA-seq)分析和实验验证,我们发现葡萄膜炎小鼠视网膜小胶质细胞和人小胶质细胞克隆3(HMC3)细胞中脂肪量和肥胖相关蛋白(FTO)的表达显着下降有炎症。此外,发现FTO敲低会加剧炎症因子的分泌和小胶质细胞的移动性/趋化性。从机制上讲,RNA-seq数据和救援实验表明磷脂酰肌醇蛋白聚糖4(GPC4)是FTO的靶标,FTO调节TLR4/NF-κB通路介导的小胶质细胞炎症。此外,RNA稳定性测定表明GPC4的上调主要是通过m 6 A“阅读器”YTH结构域家族蛋白3(YTHDF3)的下调来调节的。最后,FTO 抑制剂 FB23-2 通过促进 GPC4/TLR4/NF-κB 信号轴进一步加剧实验性自身免疫性葡萄膜炎 (EAU) 炎症,而 TLR4 抑制剂 TAK-242 可以减弱这种情况。总的来说,FTO 减少可能会促进 EAU 中的小胶质细胞炎症,这表明 FTO 功能的恢复或激活可能是葡萄膜炎的潜在治疗策略。

更新日期:2022-10-04
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