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

作者全名："He, Siyuan; Li, Wanqian; Wang, Guoqing; Wang, Xiaotang; Fan, Wei; Zhang, Zhi; Li, Na; Hou, Shengping"

作者地址："[He, Siyuan; Li, Wanqian; Wang, Guoqing; Wang, Xiaotang; Fan, Wei; Zhang, Zhi; Hou, Shengping] Chongqing Med Univ, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [He, Siyuan; Li, Wanqian; Wang, Guoqing; Wang, Xiaotang; Fan, Wei; Zhang, Zhi; Hou, Shengping] Chongqing Key Lab Ophthalmol, Chongqing 400016, Peoples R China; [He, Siyuan; Li, Wanqian; Wang, Guoqing; Wang, Xiaotang; Fan, Wei; Zhang, Zhi; Hou, Shengping] Chongqing Eye Inst, Chongqing 400016, Peoples R China; [He, Siyuan; Li, Wanqian; Wang, Guoqing; Wang, Xiaotang; Fan, Wei; Zhang, Zhi; Hou, Shengping] Natl Clin Res Ctr Ocular Dis, Chongqing Branch, Chongqing 400016, Peoples R China; [Li, Na] Chongqing Med Univ, Coll Basic Med, Chongqing 400016, Peoples R China"

通信作者："Hou, SP (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing 400016, Peoples R China.; Li, N (通讯作者)，Chongqing Med Univ, Coll Basic Med, Chongqing 400016, Peoples R China."

来源：GENES & DISEASES

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001037835500001

JCR分区：Q1

影响因子：6.9

年份：2023

卷号：10

期号：5

开始页：2179

结束页：2193

文献类型：Article

关键词：Fat mass and obesity-associated protein; Glypican 4; Microglia; N6-methyladenosine; Uveitis; YTH domain Family protein 3

摘要："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-kB 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 FB 23-2 further exacerbated experimental autoimmune uveitis (EAU) inflammation by promoting the GPC4/TLR4/NF-kB 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. 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/)."

基金机构："National Natural Science Foundation Project of China [82070951, 82271078, 81873678]; Innovative Research Group Project of Chongqing Education Commission (China) [CXQT19015]; Natural Science Foundation Project of Chongqing, China [cstc2019jcyjmsxmX0120]; Innovation Supporting Plan of Overseas Study of Chongqing, China [cx2018010]; Chongqing Education Commission (China) [KJQN202000406]; National Key Clinical Specialties Construction Program of China, Chongqing Branch of National Clinical Research Center for Ocular Diseases; Chongqing Key Laboratory of Ophthalmology (China) (CSTC) [2008CA5003]; Natural Science Foundation Project of Chongqing Medical University (China) [W0047]"

基金资助正文："This study was supported by the National Natural Science Foundation Project of China (No. 82070951, 82271078 and 81873678); the Innovative Research Group Project of Chongqing Education Commission (China) (No. CXQT19015); the Natural Science Foundation Project of Chongqing, China (No. cstc2019jcyjmsxmX0120); the Innovation Supporting Plan of Overseas Study of Chongqing, China (No. cx2018010); the Chongqing Education Commission (China) (No. KJQN202000406); the National Key Clinical Specialties Construction Program of China, Chongqing Branch of National Clinical Research Center for Ocular Diseases; the Chongqing Key Laboratory of Ophthalmology (China) (CSTC, No. 2008CA5003); and Natural Science Foundation Project of Chongqing Medical University (China) (No. W0047)."