Cardiac macrophage biology in the steady-state heart, the aging heart, and following myocardial infarction

Abstract

Macrophages play critical roles in homeostatic maintenance of the myocardium under normal conditions and in tissue repair after injury. In the steady-state heart, resident cardiac macrophages remove senescent and dying cells and facilitate electrical conduction. In the aging heart, the shift in macrophage phenotype to a proinflammatory subtype leads to inflammaging. Following myocardial infarction (MI), macrophages recruited to the infarct produce both proinflammatory and anti-inflammatory mediators (cytokines, chemokines, matrix metalloproteinases, and growth factors), phagocytize dead cells, and promote angiogenesis and scar formation. These diverse properties are attributed to distinct macrophage subtypes and polarization status. Infarct macrophages exhibit a proinflammatory M1 phenotype early and become polarized toward an anti-inflammatory M2 phenotype later post-MI. Although this classification system is oversimplified and needs to be refined to accommodate the multiple different macrophage subtypes that have been recently identified, general concepts on macrophage roles are independent of subtype classification. This review summarizes current knowledge about cardiac macrophage origins, roles, and phenotypes in the steady state, with aging, and after MI, as well as highlights outstanding areas of investigation.

Fig 1

Macrophage origins in the steady-state heart and the aging heart. In the steady state, the vast majority of resident cardiac macrophages originate from the yolk sac and fetal liver progenitors, with minimal dependence on blood monocytes as a source. In terms of subpopulations, CCR2⁺ macrophages are replenished by blood monocyte recruitment and local proliferation, whereas CCR2⁻ macrophages are repopulated largely by local proliferation. With age, self-renewal of resident cardiac macrophage declines, and blood monocytes increasingly contribute to the cardiac macrophage population.

Fig 2

Macrophage origins in the postmyocardial infarction (MI) heart. Following MI, bone marrow hematopoiesis and extramedullary hematopoiesis by the spleen produce abundant numbers of monocytes, which translocate to the circulation and are recruited to the ischemic heart. In the infarct area, the vast majority of macrophages in the first 3 days are derived from recruitment of blood monocytes, and the renewal of resident macrophages is trivial; in contrast, in the nonischemic remote myocardium, macrophages arise from both local renewal of resident macrophages and recruitment of blood monocytes. The images of cells and organs were obtained from Servier Medical Art (www.servier.com).

Fig 3

Proposed post-MI macrophage polarization mechanisms. The integration of 2 mechanisms determines the polarization status of macrophages in the MI heart. (1) M1 and M2 macrophages originate from circulating Ly6C^high and Ly6C^low monocytes, respectively; Recruitment of Ly6C^high monocytes depends on CCR2 signaling, whereas recruitment of Ly6C^low monocytes is CX3CR1 dependent; and (2) the mix of pro-M1 and pro-M2 factors existing in the MI myocardium orchestrates macrophage polarization status. MI, myocardial infarction. The images of cells and organs were obtained from Servier Medical Art (www.servier.com).