Macrophage Mertk mediates pressure overload-induced heart failure via type I interferon response

  • Biochem Biophys Res Commun. 2025 Nov 1:787:152767. doi: 10.1016/j.bbrc.2025.152767.
Yikai Cui  1 ,  Liwei Liu  1 ,  Jinyan Zhang  1 ,  Xiaoyi Zou  2 ,  Gangze Li  3 ,  Hao Jiang  1 ,  Zhifeng Yao  4 ,  Junbo Ge  5
Affiliations
  • 1. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 2. Reproductive Medicine Centre, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 3. Center of Emergency and Critical Medicine, Jinshan Hospital of Fudan University, Shanghai, 200032, China.
  • 4. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 5. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China. Electronic address: [email protected].
PMID: 41076977 DOI: 10.1016/j.bbrc.2025.152767
Abstract

Macrophages play a critical role in the pathogenesis and progression of heart failure, wherein sustained cardiomyocyte Apoptosis is a key feature. The Mer proto-oncogene tyrosine kinase (MERTK) is a critical receptor that mediates the efferocytosis of apoptotic cells by macrophages. However, the role and mechanism of action of MERTK in pressure overload-induced heart failure remains unclear. Here, we demonstrate that Mertk expression was upregulated in cardiac tissue macrophages of mice with pressure overload-induced heart failure. Deletion of Mertk ameliorated transverse aortic constriction (TAC)- and Ang II-induced cardiac hypertrophy and heart failure. This protective effect was associated with reduced type I interferon signaling and was reversed by interferon receptor activation. Efferocytosis assays were performed to demonstrate that mitochondrial double-stranded RNA from apoptotic cardiomyocytes activated Toll-like Receptor 3 in macrophages, promoting Interferon beta (Ifn-β) expression. In vitro experiment identified that Ifn-β sensitized cardiomyocytes to Ang II stimulation by augmenting the P53 pathway, suppressing Ang II-induced protective Mitophagy and promoting cardiomyocyte Apoptosis. In conclusion, macrophage Mertk receptor exacerbated post-TAC heart failure and cardiac hypertrophy by mediating the phagocytosis of apoptotic cardiomyocytes and promoting Ifn-β expression. This study provides novel insights into the role of macrophage Mertk-mediated efferocytosis and type I interferon response in the pathogenesis of heart failure. These findings highlight an unrecognized function of Mertk in pressure overload-induced cardiac remodeling and identify Ifn-β as a key downstream effector of Mertk in this pathological process.

Keywords
Efferocytosis; Heart failure; Macrophages.
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