Resident macrophages as potential therapeutic targets for cardiac ageing and injury

Abstract

Cardiac-resident macrophages (CRMs) play critical roles in maintaining cardiac homoeostasis and removing senescent and dying cells. Recent preclinical data have re-energised the area of cardioimmunology and provided improved understanding of the modulation of compositional and functional phenotypes of CRMs. These data can aid in achieving improved cardiac regeneration, repair and functional remodelling following cardiac injury. In this review, we discuss the composition and renewal of various subsets of CRMs. Specific attention has been given to delineate the roles of various CRM subsets with respect to (1) facilitation of cardiac development and maintenance of physiological function such as electrical conduction and rhythm; (2) promotion of cardiac regeneration, inflammation resolution and functional remodelling following a cardiac injury; and (3) therapeutic potential. We have also highlighted the relationship between CRM replenishment and cardiomyocyte senescence as well as cardiovascular diseases development. Finally, we have addressed future perspectives and directions in basic research and potentially clinical applications of CRMs.

Keywords: cardiac development; cardiac injury; cardiac regeneration; cardiac‐resident macrophages; cardiomyocyte senescence.

Figure 1

A diagrammatic representation showing that cardiac‐resident macrophages (CRMs) are seeded within the cardiac tissue at embryogenesis. During their lifespan, CRMs undergo three developmental waves. The first wave of embryonic macrophage development is from yolk sac around E9.5‐E10 and disappears before birth. The second wave involves the erythromyeloid precursors (EMPs) seeded in the foetal liver between E12.5 and E16.5. The third wave is bone marrow‐derived HSC (hematopoietic stem cells) from E16.5 throughout life. Under steady‐state conditions, foetal liver‐derived CRMs are maintained through in situ proliferation and decrease with age. A substantial pool of adult CRMs is replenished by monocyte‐derived macrophages and ultimately replaces embryo‐ and foetal liver‐derived cardiac macrophages. Following cardiac injury, the neonatal cardiac macrophage population expands through proliferation. However, in adults, CRMs are initially lost and replaced by recruited monocytes.

Figure 2

Diagram showing the role of cardiac‐resident macrophages (CRMs) in cardiac development and function. (a) CRMs accelerate the repolarisation of cardiomyocytes through gap junctions containing connexin‐43 (CX43), increase atrioventricular conduction, regulate cardiomyocyte proliferation, remove apoptotic cells and prevent direct ingestion of bacteria. (b) CRMs are associated with a cardiac diastolic function in ageing‐related fibrosis. Macrophages secrete stromal proteins, which are directly involved in extracellular matrix (ECM) remodelling. (c) CRMs promote angiogenesis by activating the endothelial cells. (d) CRMs patrol the vasculature and maintain vessel wall integrity. AV means atrioventricular.

Figure 3

Diagram showing the role of cardiac‐resident macrophages (CRMs) in cardiac injury. During the early stage of cardiac injury, damaged myocardium releases danger signals. Ly6C^hiCCR2⁺ monocytes are recruited at the injured sites and differentiate into inflammatory macrophages, promoting inflammation through production of proinflammatory cytokines and recruitment of neutrophils aggravating cardiac injury. During the resolution of inflammation, the resolving macrophages ameliorate the inflammation by mediating efferocytosis, secreting IL‐10 or lipoxins and by suppressing monocyte recruitment. During the last stage, inflammatory or infiltrated macrophages differentiate into tissue repair macrophages. In adults, they improve tissue repair, promote angiogenesis, activate fibroblasts and are directly involved in extracellular matrix (ECM) remodelling. In neonatal mice, CRMs promote cardiac regeneration driven by cardiomyocyte proliferation without scar formation.