Macrophages and Cardiovascular Health

Abstract

Research during the last decade has generated numerous insights on the presence, phenotype, and function of myeloid cells in cardiovascular organs. Newer tools with improved detection sensitivities revealed sizable populations of tissue-resident macrophages in all major healthy tissues. The heart and blood vessels contain robust numbers of these cells; for instance, 8% of noncardiomyocytes in the heart are macrophages. This number and the cell's phenotype change dramatically in disease conditions. While steady-state macrophages are mostly monocyte independent, macrophages residing in the inflamed vascular wall and the diseased heart derive from hematopoietic organs. In this review, we will highlight signals that regulate macrophage supply and function, imaging applications that can detect changes in cell numbers and phenotype, and opportunities to modulate cardiovascular inflammation by targeting macrophage biology. We strive to provide a systems-wide picture, i.e., to focus not only on cardiovascular organs but also on tissues involved in regulating cell supply and phenotype, as well as comorbidities that promote cardiovascular disease. We will summarize current developments at the intersection of immunology, detection technology, and cardiovascular health.

FIGURE 1.

Plethora of macrophage functions. Macrophages have a vast number of functions in different tissues, in addition to their main functions they share in all organs. We highlight some new and exciting discoveries. GIT, gastrointestinal tract; HSPCs, hematopoietic stem and progenitor cells; MHC, major histocompatibility complex; MMPs, matrix metalloproteinases; PPAR, peroxisome proliferator-activated receptor; RELM, resistin-like molecule; TIMPs, tissue inhibitors of matrix metalloproteinases; TLRs, Toll-like receptors; VCAM-1, vascular cell adhesion molecule 1.

FIGURE 2.

Macrophage origin in the brain and cardiovascular organs. The cartoon depicts important steps in the development of monocytes and tissue-resident macrophages. The main organ of hematopoiesis (yolk sac, fetal liver, and bone marrow) is indicated. The main steps in tissue-resident macrophage ontogeny, as well as the origin of specific macrophage subsets in brain, heart, and aorta, are highlighted below the schematic. Density gradients of major histocompatibility complex II (MHCII) and CX3CR1 in cardiac macrophages indicate that these decrease or increase with age, respectively. Overall proliferation capacity of cardiac macrophages decreases with age, and they are increasingly replenished by monocytes. AGM, aorta-gonad-mesonephros; E, embryonic day; EMPs, early erythromyeloid precursors; HSCs, hematopoietic stem cells. P, postnatal day.

FIGURE 3.

Macrophage origin and function in steady-state and diseased vessels. Aortic macrophage ontogeny and role during steady-state and atherosclerosis initiation and progression are illustrated for each stage. For simplicity, only the role of macrophages is depicted. The role of other immune cells, endothelial cells, and vascular smooth muscle cells is not shown. Percentages indicate contribution of monocyte recruitment or local proliferation to macrophage origin over the indicated amount of months. AngII, angiotensin II; ECs, endothelial cells; ECM, extracellular matrix; GM-CSF, granulocyte macrophage-CSF; HSPCs, hematopoietic stem and progenitors cells; LDL, low-density lipoprotein; M-CSF, macrophage-colony-stimulating factor; MHC, major histocompatibility complex; MI, myocardial infarction; MMPs, matrix metalloproteinases; NK, natural killer; NLRP, NACHT, LRR, and PYD, domains containing protein; oxLDL, oxidized LDL; SR-A, scavenger receptor A; Tet2, Tet methylcytosine dioxygenase 2; TGF, transforming growth factor; TIMPs, tissue inhibitors of matrix metalloproteinases; TLRs, Toll-like receptors.

FIGURE 4.

Macrophage origin and function in the steady-state and inflamed heart. Cardiac macrophage ontogeny and function during steady state and inflammation are depicted in the inset. For simplicity, only the role of macrophages is depicted. Macrophage turnover in the heart is governed by macrophage-colony-stimulating factor (M-CSF) and CX3CL1. A variety of soluble factors are increased in circulation after myocardial infarction, listed in the box, which result in monocyte recruitment and further increase hematopoiesis, in addition to autonomic signaling. Proliferation and differentiation of CD131+ and CCR2+ hematopoietic stem and progenitors cells (HSPCs) is increased in the bone marrow. A decrease of retention factors, for example, CXCL12, allows for mobilization of CCR2+ HSPCs to the spleen, where they are retained, for example, via vascular cell adhesion molecule 1 (VCAM-1), and further proliferate and differentiate. Monocyte release from the bone marrow is CCL2/CCR2 dependent, while release from the spleen is angiotensin II dependent. Percentages indicate contribution of bone marrow and spleen to monocytes recruited to the infarct area. CCR2+ macrophages have been indicated to recruit neutrophils, whereas B cells were found to recruit monocytes via CCL7. AT-II, angiotensin II; Cx, connexin; M-CSF, macrophage-colony-stimulating factor; MHC, major histocompatibility complex; MMPs, matrix metalloproteinases; TIMPs, tissue inhibitors of matrix metalloproteinases; TLRs, Toll-like receptors.

FIGURE 5.

Macrophage origin and function in the steady-state and injured brain. Microglia and border zone macrophage functions are illustrated in steady state and inflammation. Monocytes do not contribute to most central nervous system (CNS) macrophages in the steady state, with the exception of choroid plexus macrophages. After injury or stroke, the blood-brain barrier is disrupted, and monocytes can be recruited in large numbers and transiently give rise to macrophages. BDNF, brain-derived neurotrophic factor; ROS, reactive oxygen species.

FIGURE 6.

Monocyte and macrophage kinetics during myocardial infarction. The time course of the biphasic monocyte and macrophage response after myocardial infarction is depicted. Resident cardiac macrophages are initially lost, and recruited monocytes give rise to new macrophages. Ly-6C^hi monocytes can give rise to both inflammatory macrophages in the initial inflammatory phase and the ensuing reparative macrophages in the reparative phase. The role of Ly-6C^low monocytes is not currently known. Mediators produced by the different macrophages are shown. Reparative macrophages can induce angiogenesis, which results in cardiac restoration in neonatal mice. This regenerative ability is lost with age. In adults, reparative macrophages induce fibrosis via induction of collagen production by myofibroblasts and cardiomyocyte hypertrophy. A fine balance of these phases is crucial to prevent heart failure: On the one hand, apolipoprotein E (ApoE) knockout (KO) mice with increased inflammatory monocytes/macrophages show increased cardiac inflammation, increased necrotic debris, and reduced ventricular function. Increased reparative macrophages or chronic responses, on the other hand, can result in increased cardiac hypertrophy, fibrosis, and reduced contractile function. ECM, extracellular matrix; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor.