Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3

• Published in: The Journal of experimental medicine 2018-05, Vol.215 (5), p.1365-1382
• Main Authors: Zhang, Xingli, Wang, Yan, Yuan, Jia, Li, Ni, Pei, Siyu, Xu, Jing, Luo, Xuan, Mao, Chaoming, Liu, Junli, Yu, Tao, Gan, Shucheng, Zheng, Qianqian, Liang, Yinming, Guo, Weixiang, Qiu, Ju, Constantin, Gabriela, Jin, Jin, Qin, Jun, Xiao, Yichuan
• Format: Article
• Language: English
• Subjects: Animals; Cell activation; Colitis; Colitis - chemically induced; Colitis - metabolism; Colitis - pathology; Dextran; Dextran Sulfate; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Enhancer of Zeste Homolog 2 Protein - deficiency; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenesis, Genetic - drug effects; Experimental allergic encephalomyelitis; Gene expression; Histones - metabolism; Immune system; Indoles - pharmacology; Inflammation; Inflammation - pathology; Kinases; Lysine - metabolism; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Methylation; Mice; Microglia; Microglia - drug effects; Microglia - metabolism; Models, Biological; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; NF-κB protein; Pathogenesis; Proteins; Proteolysis - drug effects; Pyridones - pharmacology; Rodents; Signal Transduction - drug effects; SOCS-3 protein; Sodium; Sulfates; Suppressor of Cytokine Signaling 3 Protein - antagonists & inhibitors; Suppressor of Cytokine Signaling 3 Protein - metabolism; TNF Receptor-Associated Factor 6 - metabolism; Toll-like receptors; Ubiquitination
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20171417

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 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 -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.