Functional diversity of cardiac macrophages in health and disease

Macrophages make up a substantial portion of the stromal compartment of the heart in health and disease. In the past decade, the origins of these cardiac macrophages have been established as two broad populations derived from either embryonic or definitive haematopoiesis and that can be distinguished by the expression of CC-motif chemokine receptor 2 (CCR2). These cardiac macrophage populations are transcriptionally distinct and have differing cell surface markers and divergent roles in cardiac homeostasis and disease. Embryonic-derived CCR2^- macrophages are a tissue-resident population that participates in tissue development, repair and maintenance, whereas CCR2⁺ macrophages are derived from definitive haematopoiesis and contribute to inflammation and tissue damage. Studies from the past 5 years have leveraged single-cell RNA sequencing technologies to expand our understanding of cardiac macrophage diversity, particularly of the monocyte-derived macrophage populations that reside in the injured and diseased heart. Emerging technologies in spatial transcriptomics have enabled the identification of distinct disease-associated cellular neighbourhoods consisting of macrophages, other immune cells and fibroblasts, highlighting the involvement of macrophages in cell-cell communication. Together, these discoveries lend new insights into the role of specific macrophage populations in the pathogenesis of cardiac disease, which can pave the way for the identification of new therapeutic targets and the development of diagnostic tools. In this Review, we discuss the developmental origin of cardiac macrophages and describe newly identified cell states and associated cellular neighbourhoods in the steady state and injury settings. We also discuss various contributions and effector functions of cardiac macrophages in homeostasis and disease.