DNA-damaging chemotherapy depletes cardiac-resident macrophages but leads to the recruitment of protective monocyte-derived macrophages that suppress inflammation.
Do DNA-damaging chemotherapies alter cardiac-resident macrophage composition and function in mouse models?
DNA-damaging chemotherapies reshape the cardiac immune landscape by replacing embryonic-derived resident macrophages with monocyte-derived macrophages that protect against subsequent cardiac injury.
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Heart failure and ischemic heart disease represent prevalent causes of death among cancer survivors. Despite extensive use of conventional chemotherapies, a limited understanding of how these agents affect the cardiac immune landscape exists. Using mouse models, we show that DNA-damaging agents selectively deplete cardiac-resident macrophages through activation of p53 signaling and resultant necroptosis and apoptosis. Genetic lineage tracing, transcriptomic profiling, and functional studies revealed that recruited monocytes progressively reconstitute the cardiac-resident macrophage compartment, were transcriptionally distinct from embryonic-derived cardiac-resident macrophages, and conferred protection from subsequent hypertensive and ischemic cardiac injury in mice. Monocyte-derived resident-like cardiac macrophages suppressed inflammation and attenuated adverse myocardial remodeling through a type I interferon–dependent mechanism. Collectively, these findings highlight unrecognized effects of DNA-damaging chemotherapies on the cardiac immune landscape and shed light on our understanding of monocyte plasticity and resident macrophage dynamics.
He et al. (Fri,) reported a other. DNA-damaging chemotherapy depletes cardiac-resident macrophages but leads to the recruitment of protective monocyte-derived macrophages that suppress inflammation.