Dusp6 deficiency attenuates neutrophil-mediated cardiac damage in the acute inflammatory phase of myocardial infarction

Xiaohai Zhou, Chenyang Zhang, Xueying Wu, Xinli Hu, Yan Zhang, Xuelian Wang, Lixia Zheng, Peng Gao, Jianyong Du, Wen Zheng, Haibao Shang, Keping Hu, Zhengfan Jiang, Yu Nie, Shengshou Hu, Rui-Ping Xiao, Xiaojun Zhu () and Jing-Wei Xiong ()
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Xiaohai Zhou: Peking University
Chenyang Zhang: Peking University
Xueying Wu: Peking University
Xinli Hu: Peking University
Yan Zhang: Peking University
Xuelian Wang: Peking University
Lixia Zheng: Peking University
Peng Gao: Peking University
Jianyong Du: Peking University
Wen Zheng: Peking University
Haibao Shang: Peking University
Keping Hu: Chinese Academy of Medical Sciences and Peking Union Medical College
Zhengfan Jiang: Peking University
Yu Nie: Chinese Academy of Medical Sciences and Peking Union Medical College
Shengshou Hu: Chinese Academy of Medical Sciences and Peking Union Medical College
Rui-Ping Xiao: Peking University
Xiaojun Zhu: Peking University
Jing-Wei Xiong: Peking University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Dual-specificity phosphatase 6 (DUSP6) serves a specific and conserved function on the dephosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). We previously identified Dusp6 as a regenerative repressor during zebrafish heart regeneration, therefore we propose to investigate the role of this repressor in mammalian cardiac repair. Utilizing a rat strain harboring Dusp6 nonsense mutation, rat neutrophil-cardiomyocyte co-culture, bone marrow transplanted rats and neutrophil-specific Dusp6 knockout mice, we find that Dusp6 deficiency improves cardiac outcomes by predominantly attenuating neutrophil-mediated myocardial damage in acute inflammatory phase after myocardial infarction. Mechanistically, Dusp6 is transcriptionally activated by p38-C/EBPβ signaling and acts as an effector for maintaining p-p38 activity by down-regulating pERK and p38-targeting phosphatases DUSP1/DUSP16. Our findings provide robust animal models and novel insights for neutrophil-mediated cardiac damage and demonstrate the potential of DUSP6 as a therapeutic target for post-MI cardiac remodeling and other relevant inflammatory diseases.

Date: 2022
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DOI: 10.1038/s41467-022-33631-z

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