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.

双特异性磷酸酶 6 (DUSP6) 对细胞外信号调节激酶 1/2 (ERK1/2) 的去磷酸化具有特定和保守的功能。我们之前将 Dusp6 鉴定为斑马鱼心脏再生过程中的再生抑制因子，因此我们建议研究该抑制因子在哺乳动物心脏修复中的作用。利用携带Dusp6无义突变的大鼠品系、大鼠中性粒细胞-心肌细胞共培养、骨髓移植大鼠和中性粒细胞特异性Dusp6敲除小鼠，我们发现Dusp6缺乏主要通过减轻急性炎症期中性粒细胞介导的心肌损伤来改善心脏结局心肌梗塞。从机械上讲，Dusp6由 p38-C/EBPβ 信号转录激活，并通过下调 pERK 和 p38 靶向磷酸酶 DUSP1/DUSP16 作为维持 p-p38 活性的效应子。我们的研究结果为中性粒细胞介导的心脏损伤提供了稳健的动物模型和新见解，并证明了 DUSP6 作为 MI 后心脏重塑和其他相关炎症性疾病的治疗靶标的潜力。