Oncotarget

Research Papers:

Identification of the histone lysine demethylase KDM4A/JMJD2A as a novel epigenetic target in M1 macrophage polarization induced by oxidized LDL

Xue Wang, Siqing Wang, Gang Yao, Dehai Yu, Kexin Chen, Qian Tong, Long Ye, Chuan Wu, Yue Sun, Haixia Li, Dirk M. Hermann, Thorsten R. Doeppner, Fengyan Jin, Yun Dai _ and Jiang Wu

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Oncotarget. 2017; 8:114442-114456. https://doi.org/10.18632/oncotarget.17748

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Abstract

Xue Wang1, Siqing Wang2, Gang Yao3, Dehai Yu4, Kexin Chen5, Qian Tong6, Long Ye7, Chuan Wu8, Yue Sun9, Haixia Li1, Dirk M. Hermann10, Thorsten R. Doeppner11, Fengyan Jin8, Yun Dai9 and Jiang Wu1

1Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin, China

2Department of Cancer Immunology, Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, Jilin, China

3Department of Neurology, the Second Hospital of Jilin University, Changchun, Jilin, China

4Cancer Center, the First Hospital of Jilin University, Changchun, Jilin, China

5Department of Immunology, Institute of Translational Medicine, the First Hospital of Jilin University, Changchun, Jilin, China

6Department of Cardiology, the First Hospital of Jilin University, Changchun, Jilin, China

7Department of Spine Surgery, the First Hospital of Jilin University, Changchun, Jilin, China

8Department of Hematology, Cancer Center, the First Hospital of Jilin University, Changchun, Jilin, China

9Laboratory of Cancer Precision Medicine, Cancer Center, the First Hospital of Jilin University, Changchun, Jilin, China

10Department of Neurology, University of Duisburg-Essen, Essen, Germany

11Department of Neurology, University of Göttingen Medical School, Göttingen, Germany

Correspondence to:

Yun Dai, email: YUN.DAI@vcuhealth.org

Fengyan Jin, email: fengyanjin@jlu.edu.cn

Jiang Wu, email: doctorwujiang@sina.cn

Keywords: KDM4A/JMJD2A, oxidized low density lipoprotein, macrophage polarization, inflammation, atherosclerosis

Received: March 14, 2017     Accepted: April 12, 2017     Published: May 10, 2017

ABSTRACT

Oxidized low density lipoprotein (oxLDL) induces macrophage activation, an event essential for atherosclerosis. Emerging evidence supports that epigenetic regulation plays important roles in macrophage activation and function. However, it remains unclear which epigenetic modulator is responsible for oxLDL-induced macrophage activation. Here, we identify for the first time KDM4A (JMJD2A) as an epigenetic modifying enzyme that controls oxLDL-induced pro-inflammatory M1 polarization of macrophages. OxLDL triggered M1 polarization of murine and human macrophages, characterized by expression of iNOS and robust production of inflammatory cytokines (e.g., TNF-α, MCP-1, IL-1β). In contrast, protein level of the M2 marker Arg1 was clearly decreased after treated with oxLDL. Notably, exposure to oxLDL resulted in markedly increased expression of KDM4A in macrophages. Functionally, shRNA knockdown of KDM4A significantly impaired M1 polarization and expression of inflammatory cytokines induced by oxLDL, accompanied by increased expression of Arg1 and VEGF. However, inhibition of KDM4A by shRNA or the pan-selective KDM inhibitor JIB-04 did not affect oxLDL-mediated activation of the NF-κB and hypoxia inducible factor (HIF) pathways, and vice versa. In addition, JIB-04 induced apoptosis of macrophages in a dose-dependent manner, an event attenuated by oxLDL. Together, these findings argue that KDM4A might represent a novel epigenetic modulator that acts to direct oxLDL-induced M1 polarization of macrophages, while its up-regulation is independent of NF-κB and HIF activation, two signals critical for pro-inflammatory activation of macrophages. They also suggest that KDM4A might serve as a potential target for epigenetic therapy in prevention and treatment of inflammatory diseases such as atherosclerosis.


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