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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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2018
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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. |
format | Online Article Text |
id | pubmed-5940261 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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