Differential Contribution of Monocytes to Heart Macrophages in Steady-State and After Myocardial Infarction
Rationale: Macrophages populate the steady-state myocardium. Previously, all macrophages were thought to arise from monocytes; however, it emerged that in several organs tissue-resident macrophages may self-maintain through local proliferation.
Objective: To study the contribution of monocytes to cardiac resident macrophages in steady-state, after macrophage depletion in CD11bDTR/+ mice and in myocardial infarction.
Methods and Results: Using in vivo fate mapping and flow cytometry, we estimated that during steady-state the heart macrophage population turns over in about one month. To explore the source of cardiac resident macrophages, we joined the circulation of mice using parabiosis. After 6 weeks, we observed blood monocyte chimerism of 35.3±3.4% while heart macrophages showed a much lower chimerism of 2.7±0.5% (p<0.01). Macrophages self renewed locally through proliferation: 2.1±0.3% incorporated BrdU 2 hours after a single injection and 13.7±1.4% heart macrophages stained positive for the cell cycle marker Ki67. The cells likely participate in defense against infection, as we found them to ingest fluorescently labeled bacteria. In ischemic myocardium, we observed that tissue resident macrophages died locally while some also migrated to hematopoietic organs. If the steady-state was perturbed by coronary ligation or diphtheria toxin-induced macrophage depletion in CD11bDTR/+ mice, blood monocytes replenished heart macrophages. However, in the chronic phase after myocardial infarction, macrophages residing in the infarct were again independent from the blood monocyte pool, returning to the steady-state situation.
Conclusions: In this study we show differential contribution of monocytes to heart macrophages during steady-state, after macrophage depletion or in the acute and chronic phase after myocardial infarction. We found that macrophages participate in the immunosurveillance of myocardial tissue. These data correspond with previous studies on tissue-resident macrophages and raise important questions on the fate and function of macrophages during the development of heart failure.
- Received January 27, 2014.
- Revision received April 25, 2014.
- Accepted May 1, 2014.