Feng Dong, Dong Yanhan, Song Yiran, Yapundich Nicholas, Xie Yifang, Spurlock Brian, Lyu Tingting, Kuehn Landry, Qian Li, Liu Jiandong
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA.
Development. 2025 Oct 15;152(20). doi: 10.1242/dev.204395. Epub 2025 Jul 11.
Recent findings have highlighted the complex role of inflammation in zebrafish heart regeneration, demonstrating that although inflammation is essential for initiating transient fibrosis and tissue repair, chronic inflammation, and unresolved fibrosis, could impede full regenerative recovery. In this study, we identified the nuclear receptor Nr4a1 as a crucial regulator of this regenerative process in zebrafish. Loss of Nr4a1 function led to a prolonged and excessive inflammatory response, disrupted neutrophil migration, delayed fibrin clearance, and ultimately impaired heart regeneration. Transcriptome-wide RNA-seq analysis at different injury stages revealed molecular disruptions associated with dysregulated inflammation and fibrosis in nr4a1 mutants. Notably, partial inhibition of the pro-inflammatory cytokine Tnfα rescued heart regeneration in the nr4a1 mutants, highlighting the therapeutic potential of modulating inflammation. Our findings suggest that Nr4a1 plays a crucial role in orchestrating the immune response during heart regeneration and may serve as a valuable target for enhancing cardiac repair following injury.
最近的研究结果突出了炎症在斑马鱼心脏再生中的复杂作用，表明尽管炎症对于启动短暂性纤维化和组织修复至关重要，但慢性炎症和未解决的纤维化可能会阻碍完全的再生恢复。在本研究中，我们确定核受体Nr4a1是斑马鱼这一再生过程的关键调节因子。Nr4a1功能丧失导致炎症反应延长和过度，破坏中性粒细胞迁移，延迟纤维蛋白清除，并最终损害心脏再生。在不同损伤阶段进行的全转录组RNA测序分析揭示了nr4a1突变体中与炎症和纤维化失调相关的分子紊乱。值得注意的是，促炎细胞因子Tnfα的部分抑制挽救了nr4a1突变体的心脏再生，突出了调节炎症的治疗潜力。我们的研究结果表明，Nr4a1在心脏再生过程中协调免疫反应方面发挥着关键作用，并且可能作为增强损伤后心脏修复的有价值靶点。
