DNA-damaging chemotherapy reshapes cardiac-resident macrophage composition and function

Area of Science:

• Cardiovascular immunology
• Cancer therapy side effects
• Macrophage biology

Background:

• Heart failure and ischemic heart disease are major causes of death in cancer survivors.
• Conventional chemotherapies' impact on the cardiac immune system is poorly understood.
• DNA-damaging agents are widely used in cancer treatment.

Purpose of the Study:

• To investigate the effects of DNA-damaging chemotherapies on cardiac-resident macrophages.
• To understand the mechanisms of cardiac immune system reconstitution after chemotherapy.
• To explore the protective functions of newly recruited cardiac macrophages.

Main Methods:

• Mouse models of chemotherapy exposure.
• Genetic lineage tracing to track cell origins.
• Transcriptomic profiling to analyze gene expression.
• Functional assays to assess cardiac injury and protection.

Main Results:

• DNA-damaging agents induce p53-dependent depletion of cardiac-resident macrophages via necroptosis and apoptosis.
• Recruited monocytes repopulate the cardiac macrophage compartment.
• Monocyte-derived macrophages are transcriptionally distinct from embryonic-derived macrophages.
• These monocyte-derived macrophages protect against hypertensive and ischemic cardiac injury.
• They suppress inflammation and adverse remodeling through type I interferon signaling.

Conclusions:

• DNA-damaging chemotherapies profoundly alter the cardiac immune landscape by depleting resident macrophages.
• Monocyte plasticity allows for the reconstitution of a protective cardiac macrophage pool.
• These findings enhance understanding of chemotherapy cardiotoxicity and macrophage dynamics.