Monocyte-Macrophages and T Cells in Atherosclerosis

Abstract

Atherosclerosis is an arterial disease process characterized by the focal subendothelial accumulation of apolipoprotein-B-containing lipoproteins, immune and vascular wall cells, and extracellular matrix. The lipoproteins acquire features of damage-associated molecular patterns and trigger first an innate immune response, dominated by monocyte-macrophages, and then an adaptive immune response. These inflammatory responses often become chronic and non-resolving and can lead to arterial damage and thrombosis-induced organ infarction. The innate immune response is regulated at various stages, from hematopoiesis to monocyte changes and macrophage activation. The adaptive immune response is regulated primarily by mechanisms that affect the balance between regulatory and effector T cells. Mechanisms related to cellular cholesterol, phenotypic plasticity, metabolism, and aging play key roles in affecting these responses. Herein, we review select topics that shed light on these processes and suggest new treatment strategies.

Keywords: Innate and adaptive inflammatory responses drive the progression of atherosclerosis; T cell; adaptive immunity; effector T cell; inflammation; innate immunity; macrophage; monocyte; regulatory T cell; which is the root cause of most cardiovascular disease. Tabas and Lichtman review the roles and regulation of monocyte-macrophages and T cells during the various stages of atherosclerosis and discuss how this knowledge suggests new therapeutic approaches.atherosclerosis.

Figure 1. Regulation of Innate Immune Processes Related to Monocyte-Macrophages in Atherosclerosis

Lesional macrophages originate from bone marrow-derived hematopoietic stem cells, which give rise to circulating monocytes. In certain instances, these stem cells first populate the spleen and then undergo extramedullary hematopoiesis. Proliferation and release of hematopoietic stem cells can be exacerbated by elevation of cellular cholesterol and by somatic mutations leading to clonal hematopoiesis, such as those that occur in aging and myeloproliferative disease (MPD). This process can also be stimulated by stress-induced sympathetic nervous system (SNS) activation. The major subpopulation of monocytes that contribute to atherosclerosis progress are Ly6c^hi monocytes, which enter lesions in response to subendothelially retained apoB-lipoproteins (LP) and subsequent chemokine release by activated endothelial cells. After differentiation into macrophages, they undergo a variety of phenotypic changes under the influence of the factors listed in the figure. Those macrophages on the inflammatory end of the spectrum secrete proteins and carry out processes that promote atherosclerosis progression, while those on the resolution end of the spectrum promote lesion regression. See text for details.

Figure 2. Intracellular Effects of Excess Cholesterol on Myeloid Cells and T Cells That Influence Atherosclerosis

In the setting of hypercholesterolemia or defects in cholesterol efflux, hematopoietic stem and progenitor cells (HSPCs) accumulate excess cholesterol. The consequence is enhanced IL-3 and GM-CSF growth factor signaling, leading to HSPC proliferation and monocytosis. With aging, clonal hematopoiesis can occur owing to loss-of-function mutations in a number of genes, including TET2. This process also contributes to monocytosis. Monocytosis is associated with increased accumulation of inflammatory monocyte-derived macrophages in atherosclerotic lesions and higher risk of atherosclerotic vascular disease in humans. These lesional macrophages are also subject to intracellular cholesterol accumulation owing to their internalization of subendothelial apoB LPs. Excess cholesterol in macrophages has multiple effects that enhance lesion inflammation, including toll-like receptor (TLR) and inflammasome activation. The result is increased production of inflammatory chemokines and cytokines, including inflammasome-derived IL-1β and IL-1β-induced IL-6 production. Moreover, changes associated with clonal hematopoiesis, e.g., loss of TET2 function, can also activate the inflammasome in macrophages, further fueling lesional inflammation. T cells do not have the capacity to accumulate large amounts of excess cholesterol, but several studies have shown that perturbations of T cell cholesterol metabolism can affect T cell differentiation and activation. Impaired ABCG1 cholesterol efflux from T cells results in enhanced Treg differentiation which reduces atherosclerotic lesion development and inflammation. In contrast, impaired esterification of cholesterol by deficiency or inhibition of acyl-coenzyme A:cholesterol acyltransferase (ACAT) increases CD8 effector T cell lipid raft formation and thereby enhances immune synapse formation and killing functions of these cells. The net effect of increases in T cell cholesterol on lesion development and inflammation are likely to reflect changes in the Teff:Treg balance and the influence of Teff cells on lesional macrophages.

Figure 3. Regulation and Impact of Adaptive Immune Processes Related to T cells in Atherosclerosis

T lymphocyte responses that affect atherosclerosis include a balance between inflammatory effector T cells, mainly interferon γ-producing T helper (Th) cells, and anti-inflammatory regulatory T cells (Treg). Pro-atherogenic Th effector cells differentiate from thymic-derived naïve T cell precursors in secondary lymphoid organs (SLOs) such as lymph nodes, in responses to antigen presentation of LDL-derived peptides by dendritic cells (DC), some of which may have migrated from the arterial wall. Treg develop in the thymus, and peripheral Treg (pTreg) can also be differentiated from peripheral naive T cells in SLOs. The direction of differentiation of naïve T cells into different Th subsets and Treg in SLOs can be influenced by systemic and local metabolic conditions. Treg and Th cells migrate into developing atherosclerotic lesions and modulate the local inflammatory microenvironment, in large part by influencing macrophage phenotypes. Conversely, resolving or inflammatory macrophage phenotypes can shift the plaque T cell balance toward Treg and Th phenotypes, respectively. Change in Treg-Th cell balance may reflect phenotypic plasticity by permitting re-differentiation between regulatory and inflammatory phenotypes, which is also influenced by systemic and plaque metabolic conditions. See text for details.