FTO-mediated m6A modification alleviates autoimmune uveitis by regulating microglia phenotypes via the GPC4/TLR4/NF-κB signaling axis

Siyuan He; Wanqian Li; Guoqing Wang; Xiaotang Wang; Wei Fan; Zhi Zhang; Na Li; Shengping Hou

doi:10.1016/j.gendis.2022.09.008

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FTO-mediated m6A modification alleviates autoimmune uveitis by regulating microglia phenotypes via the GPC4/TLR4/NF-κB signaling axis

Full-length article | 更新时间：2023-08-29

- FTO-mediated m6A modification alleviates autoimmune uveitis by regulating microglia phenotypes via the GPC4/TLR4/NF-κB signaling axis
- Genes & Diseases Vol. 10, Issue 5, (2023)
- 作者机构：
  
  1. Chongqing Eye Institute,Chongqing,China,400016
  2. The First Affiliated Hospital of Chongqing Medical University,Chongqing,China,400016
  3. Chongqing Branch of National Clinical Research Center for Ocular Diseases,Chongqing,China,400016
  4. College of Basic Medicine, Chongqing Medical University,Chongqing,China,400016
  5. Chongqing Key Laboratory of Ophthalmology,Chongqing,China,400016
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2022.09.008
  CLC：
- Published：2023，
  
  Published Online：1 September 2023，
扫描看全文
Siyuan He, Wanqian Li, Guoqing Wang, et al. FTO-mediated m6A modification alleviates autoimmune uveitis by regulating microglia phenotypes via the GPC4/TLR4/NF-κB signaling axis. [J]. Genes & Diseases 10(5).(2023)
DOI：

Siyuan He, Wanqian Li, Guoqing Wang, et al. FTO-mediated m6A modification alleviates autoimmune uveitis by regulating microglia phenotypes via the GPC4/TLR4/NF-κB signaling axis. [J]. Genes & Diseases 10(5).(2023) DOI： 10.1016/j.gendis.2022.09.008.

摘要

Abstract

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 (m

A) modification has been proven to be involved in the immune response. Therefore

we in this work aimed to identify the potentially crucial m

A 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 m

A “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.

关键词

Keywords

Fat mass and obesity-associated proteinGlypican 4MicrogliaN6-methyladenosineuveitisYTH domain Family protein 3

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