RNF149 Destabilizes IFNGR1 in Macrophages to Favor Postinfarction Cardiac Repair

作者：Chun-Kai Huang, Zhiyong Chen, Zhongxing Zhou, Shuaijie Chen, Longqing Chen, Liliang Li, Tao Li, Xiaoxiang Yan, Dajun Chai · 发表于：Circulation Research · 年份：2024 · DOI：10.1161/circresaha.123.324023 · 被引用次数：20 · 研究领域：Cardiac Fibrosis and Remodeling、Cardiac Structural Anomalies and Repair、Congenital heart defects research

BACKGROUND: Macrophage-driven inflammation critically involves in cardiac injury and repair following myocardial infarction (MI). However, the intrinsic mechanisms that halt the immune response of macrophages, which is critical to preserve homeostasis and effective infarct repair, remain to be fully defined. Here, we aimed to determine the ubiquitination-mediated regulatory effects on averting exaggerated inflammatory responses in cardiac macrophages. METHODS: We used transcriptome analysis of mouse cardiac macrophages and bone marrow–derived macrophages to identify the E3 ubiquitin ligase RNF149 (ring finger protein 149) as a modulator of macrophage response to MI. Employing loss-of-function methodologies, bone marrow transplantation approaches, and adenovirus-mediated RNF149 overexpression in macrophages, we elucidated the functional role of RNF149 in MI. We explored the underlying mechanisms through flow cytometry, transcriptome analysis, immunoprecipitation/mass spectrometry analysis, and functional experiments. RNF149 expression was measured in the cardiac tissues of patients with acute MI and healthy controls. RESULTS: RNF149 was highly expressed in murine and human cardiac macrophages at the early phase of MI. Knockout of RNF149, transplantation of Rnf149 –/– bone marrow, and bone marrow macrophage–specific RNF149-knockdown markedly exacerbated cardiac dysfunction in murine MI models. Conversely, overexpression of RNF149 in macrophages attenuated the ischemia-induced d...