Single-cell transcriptomic analyses of cardiac immune cells reveal that Rel-driven CD72-positive macrophages induce cardiomyocyte injury

Aims: The goal of our study was to investigate the heterogeneity of cardiac macrophages (CMus) in mice with transverse aortic constriction (TAC) via single-cell sequencing and identify a subset of macrophages associated with heart injury. . Methods: We selected all CMus from CD45þ cells using single-cell mRNA sequencing data. Through dimension reduction, and results clustering, and enrichment analyses, CD72hi CMus were identified as a subset of pro-inflammatory macrophages. The pseudo-time trajectory and ChIP-Seq analyses identified Rel as the key transcription factor that induces CD72hi CMu differentiation. Rel KD and Rel-/- bone marrow chimaera mice subjected to TAC showed features of mitigated cardiac injury, including decreased levels of cytokines and ROS, which prohibited cardiomyocyte death. The transfer of adoptive Rel-overexpressing monocytes and CD72hi CMu injection directly aggravated heart injury in the TAC model. The CD72hi macrophages also exerted pro-inflammatory and cardiac injury effects associated with myocardial infarction. In humans, patients with heart failure exhibit increased CD72hi CMu levels following dilated cardiomyopathy and ischaemic cardiomyopathy. Conclusion: Bone marrow-derived, Rel-mediated CD72hi macrophages play a pro-inflammatory role, induce cardiac injury and, thus, may serve as a therapeutic target for multiple cardiovascular diseases.