1. Academic Validation
  2. YY1 Lactylation Aggravates Autoimmune Uveitis by Enhancing Microglial Functions via Inflammatory Genes

YY1 Lactylation Aggravates Autoimmune Uveitis by Enhancing Microglial Functions via Inflammatory Genes

  • Adv Sci (Weinh). 2024 Mar 17:e2308031. doi: 10.1002/advs.202308031.
Jiaxing Huang 1 Xiaotang Wang 1 Na Li 2 Wei Fan 1 Xingran Li 1 Qian Zhou 1 Jiangyi Liu 1 Wanqian Li 1 Zhi Zhang 1 Xiaoyan Liu 1 Shuhao Zeng 1 Hui Yang 3 Meng Tian 3 Peizeng Yang 1 Shengping Hou 3
Affiliations

Affiliations

  • 1 Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute; Chongqing Branch of National Clinical Research Center for Ocular Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 2 Department of Laboratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, 100005, China.
  • 3 Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
Abstract

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.

Keywords

Yin-Yang 1; autoimmune uveitis; inflammation; lactylation; microglia.

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