YY1 Lactylation Aggravates Autoimmune Uveitis by Enhancing Microglial Functions via Inflammatory Genes
作者全名："Huang, Jiaxing; Wang, Xiaotang; Li, Na; Fan, Wei; Li, Xingran; Zhou, Qian; Liu, Jiangyi; Li, Wanqian; Zhang, Zhi; Liu, Xiaoyan; Zeng, Shuhao; Yang, Hui; Tian, Meng; Yang, Peizeng; Hou, Shengping"
作者地址："[Huang, Jiaxing; Wang, Xiaotang; Fan, Wei; Li, Xingran; Zhou, Qian; Liu, Jiangyi; Li, Wanqian; Zhang, Zhi; Liu, Xiaoyan; Zeng, Shuhao; Yang, Peizeng] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Eye Inst, Chongqing Key Lab Ophthalmol, Chongqing 400016, Peoples R China; [Huang, Jiaxing; Wang, Xiaotang; Fan, Wei; Li, Xingran; Zhou, Qian; Liu, Jiangyi; Li, Wanqian; Zhang, Zhi; Liu, Xiaoyan; Zeng, Shuhao; Yang, Peizeng] Chongqing Med Univ, Affiliated Hosp 1, Natl Clin Res Ctr Ocular Dis, Chongqing Branch, Chongqing 400016, Peoples R China; [Li, Na] Capital Med Univ, Beijing Tongren Hosp, Dept Lab Med, Beijing 100005, Peoples R China; [Yang, Hui; Tian, Meng; Hou, Shengping] Capital Med Univ, Beijing Tongren Hosp, Beijing Tongren Eye Ctr, Beijing Ophthalmol & Visual Sci Key Lab,Beijing In, Beijing 100730, Peoples R China"
通信作者："Yang, PZ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing Eye Inst, Chongqing Key Lab Ophthalmol, Chongqing 400016, Peoples R China.; Yang, PZ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Natl Clin Res Ctr Ocular Dis, Chongqing Branch, Chongqing 400016, Peoples R China.; Hou, SP (通讯作者)，Capital Med Univ, Beijing Tongren Hosp, Beijing Tongren Eye Ctr, Beijing Ophthalmol & Visual Sci Key Lab,Beijing In, Beijing 100730, Peoples R China."
来源：ADVANCED SCIENCE
ESI学科分类：PHYSICS
WOS号：WOS:001186256800001
JCR分区：Q1
影响因子：14.3
年份：2024
卷号：
期号：
开始页：
结束页：
文献类型：Article; Early Access
关键词：autoimmune uveitis; inflammation; lactylation; microglia; Yin-Yang 1
摘要："Activated microglia in the retina are essential for the development of autoimmune uveitis. Yin-Yang 1 (YY1) is an important transcription factor that participates in multiple inflammatory and immune-mediated diseases. Here, an increased YY1 lactylation in retinal microglia within in the experimental autoimmune uveitis (EAU) group is observed. YY1 lactylation contributed to boosting microglial activation and promoting their proliferation and migration abilities. Inhibition of lactylation suppressed microglial activation and attenuated inflammation in EAU. Mechanistically, cleavage under targets & tagmentation (CUT&Tag? analysis revealed that YY1 lactylation promoted microglial activation by regulating the transcription of a set of inflammatory genes, including STAT3, CCL5, IRF1, IDO1, and SEMA4D. In addition, p300 is identified as the writer of YY1 lactylation. Inhibition of p300 decreased YY1 lactylation and suppressed microglial inflammation in vivo and in vitro. Collectively, the results showed that YY1 lactylation promoted microglial dysfunction in autoimmune uveitis by upregulating inflammatory cytokine secretion and boosting cell migration and proliferation. Therapeutic effects can be achieved by targeting the lactate/p300/YY1 lactylation/inflammatory genes axis. This study reveals that YY1 lactylation promotes microglial functions in autoimmune uveitis by upregulating inflammatory cytokine secretion and boosting cell migration and proliferation. Therefore, inhibiting YY1 lactylation genetically or pharmacologically alleviates symptoms of EAU and mitigates activation of microglia, indicating that therapeutic effects can be achieved by targeting the lactate/p300/YY1 lactylation and inflammatory gene (IRF1/IDO1/SEMA4D/CCL5/STAT3) axis. image"
基金机构："National Natural Science Foundation [82070951, 82271078, 82371045]; National Natural Science Foundation Project of China [JYY2023-6]; Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes; National Key Clinical Specialties Construction Program of China, Chongqing Branch of National Clinical Research Center for Ocular Diseases [2008CA5003]; Chongqing Key Laboratory of Ophthalmology (CSTC)"
基金资助正文："This work was supported by the National Natural Science Foundation Project of China (82070951, 82271078, 82371045), Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes (PWD&RPP-MRI, JYY2023-6), National Key Clinical Specialties Construction Program of China, Chongqing Branch of National Clinical Research Center for Ocular Diseases, and Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003)."
