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

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 (IFNb) expression. In vitro experiment identified that IFNb 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 IFNb 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 IFNb as a key downstream effector of MERTK in this pathological process rna-seq profiling of hearts of wildtype and Mertk knockdown c57 mice at 8 weeks after transverse aortic constriction

巨噬细胞在心力衰竭的发病机制与疾病进展中发挥关键作用，而持续的心肌细胞凋亡是心力衰竭的核心特征之一。MER原癌基因酪氨酸激酶（MER proto-oncogene tyrosine kinase, MERTK）是介导巨噬细胞吞噬凋亡细胞的关键受体。然而，MERTK在压力超负荷诱导型心力衰竭中的作用与具体分子机制仍未明确。本研究发现，在压力超负荷诱导型心力衰竭的小鼠模型中，其心脏组织巨噬细胞内的MERTK表达水平显著上调。敲除MERTK可改善主动脉弓缩窄（transverse aortic constriction, TAC）以及血管紧张素II（Angiotensin II, Ang II）诱导的心肌肥厚与心力衰竭。该保护效应与I型干扰素信号通路活性降低相关，而激活干扰素受体可抵消这一保护作用。我们通过胞葬作用（efferocytosis）实验证实，凋亡心肌细胞释放的线粒体双链RNA可激活巨噬细胞内的Toll样受体3（Toll-like receptor 3, TLR3），进而促进β干扰素（Interferon beta, IFNB）的表达。体外实验表明，IFNB可通过激活P53通路增强心肌细胞对Ang II刺激的敏感性：一方面抑制Ang II诱导的保护性线粒体自噬（mitophagy），另一方面促进心肌细胞凋亡。综上，巨噬细胞表面的MERTK受体可通过介导凋亡心肌细胞的吞噬作用并促进IFNB表达，加重主动脉弓缩窄术后的心力衰竭与心肌肥厚。本研究为阐明巨噬细胞MERTK介导的胞葬作用与I型干扰素应答在心力衰竭发病机制中的作用提供了全新视角。本研究结果揭示了MERTK在压力超负荷诱导的心肌重构中此前未被认知的功能，并证实IFNB是该病理过程中MERTK的关键下游效应分子。本数据集包含主动脉弓缩窄术后8周时，野生型与Mertk敲低型C57小鼠的心脏组织RNA测序（RNA-seq）表达谱数据。