2. Academic Validation
  3. Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3

Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3

  • J Exp Med. 2018 May 7;215(5):1365-1382. doi: 10.1084/jem.20171417.
Xingli Zhang 1,  Yan Wang 1,  Jia Yuan 1,  Ni Li 2,  Siyu Pei 1,  Jing Xu 1,  Xuan Luo 3,  Chaoming Mao 3,  Junli Liu 1,  Tao Yu 1,  Shucheng Gan 1,  Qianqian Zheng 4,  Yinming Liang 4,  Weixiang Guo 5,  Ju Qiu 1,  Gabriela Constantin 6,  Jin Jin 7,  Jun Qin 8,  Yichuan Xiao 9
Affiliations

Affiliations

  • 1 The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 2 The Key Laboratory of Stem Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 3 Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China.
  • 4 School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.
  • 5 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  • 6 Department of Medicine, Section of General Pathology, University of Verona, Verona, Italy.
  • 7 Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 8 The Key Laboratory of Stem Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China qinjun@sibs.ac.cn.
  • 9 The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China ycxiao@sibs.ac.cn.
PMID: 29626115 DOI: 10.1084/jem.20171417
Abstract

Histone 3 Lys27 (H3K27) trimethyltransferase EZH2 is implicated in the pathogenesis of autoimmune inflammation. Nevertheless, the role of EZH2 in macrophage/microglial activation remains to be defined. In this study, we identified that macrophage/microglial H3K27me3 or EZH2, rather than functioning as a repressor, mediates Toll-like Receptor (TLR)-induced proinflammatory gene expression, and therefore EZH2 depletion diminishes macrophage/microglial activation and attenuates the autoimmune inflammation in dextran sulfate sodium-induced colitis and experimental autoimmune encephalomyelitis. Mechanistic characterizations indicated that EZH2 deficiency directly stimulates suppressor of cytokine signaling 3 (Socs3) expression and therefore enhances the Lys48-linked ubiquitination and degradation of tumor necrosis factor receptor-associated factor 6. As a consequence, TLR-induced MyD88-dependent nuclear factor κB activation and the expression of proinflammatory genes in macrophages/microglia are compromised in the absence of EZH2. The functional dependence of EZH2 for Socs3 is further illustrated by the rescue experiments in which silencing of Socs3 restores macrophage activation and rescues autoimmune inflammation in macrophage/microglial EZH2-deficient mice. Together, these findings establish EZH2 as a macrophage lineage-specific mediator of autoimmune inflammation and highlight a previously unknown mechanism of EZH2 function.

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