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Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940261/
https://www.ncbi.nlm.nih.gov/pubmed/29626115
http://dx.doi.org/10.1084/jem.20171417
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author 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
author_facet 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
author_sort Zhang, Xingli
collection PubMed
description 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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spelling pubmed-59402612018-11-07 Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3 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 J Exp Med Research Articles 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. Rockefeller University Press 2018-05-07 /pmc/articles/PMC5940261/ /pubmed/29626115 http://dx.doi.org/10.1084/jem.20171417 Text en © 2018 Zhang et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
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
Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3
title Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3
title_full Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3
title_fullStr Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3
title_full_unstemmed Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3
title_short Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3
title_sort macrophage/microglial ezh2 facilitates autoimmune inflammation through inhibition of socs3
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940261/
https://www.ncbi.nlm.nih.gov/pubmed/29626115
http://dx.doi.org/10.1084/jem.20171417
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