Background: Tissue-resident macrophages play an essential role in health and disease. They originate from hematopoietic progenitors of the yolk sac (YS) as well as from definitive bone marrow (BM) hematopoiesis. Consequently, macrophages of YS and BM origin are present in adult organs, both contributing to homeostatic and immune functions throughout life. However, the association of the developmental origin of macrophages with their phenotype and functions has remained incompletely understood.

Methods and Results: To determine the influence of ontogeny on transcriptional profiles in cardiac macrophages, we combined non-irradiation BM chimera and novel fate mapping models with deep immune phenotyping. Resident macrophages differ from their recruited counterparts and are equipped with transcriptional programs that promote tissue homeostasis and immune surveillance. In the acute response to ischemia and reperfusion (I/R) injury, infiltrating BM-derived macrophages represent the major population and exhibit inflammatory and host defense-related properties. In accordance to their function in homeostasis, resident macrophages show a reparative gene profile after I/R injury. To evaluate their role in health and disease, we applied a genetic model, in which resident cardiac macrophages are largely depleted due to a deletion of the fms-intronic regulatory element (FIRE) in the Csf1r gene. Beyond the numerical reduction in resident macrophages (~80%), single cell RNA-sequencing studies of the whole cardiac immune cell population show that these changes lead to alterations in the cardiac immune phenotype with reduced anti-inflammatory properties. These transcriptional changes are associated with an aggravated adverse remodelling in response to I/R. 

Conclusion: In summary, we here define the immune signature of cardiac macrophage populations in relation to their developmental paths and provide evidence of the importance of resident macrophages in homeostasis and tissue repair.