How the immune system shapes atherosclerosis: roles of innate and adaptive immunity

Abstract

Atherosclerosis is the root cause of many cardiovascular diseases. Extensive research in preclinical models and emerging evidence in humans have established the crucial roles of the innate and adaptive immune systems in driving atherosclerosis-associated chronic inflammation in arterial blood vessels. New techniques have highlighted the enormous heterogeneity of leukocyte subsets in the arterial wall that have pro-inflammatory or regulatory roles in atherogenesis. Understanding the homing and activation pathways of these immune cells, their disease-associated dynamics and their regulation by microbial and metabolic factors will be crucial for the development of clinical interventions for atherosclerosis, including potentially vaccination-based therapeutic strategies. Here, we review key molecular mechanisms of immune cell activation implicated in modulating atherogenesis and provide an update on the contributions of innate and adaptive immune cell subsets in atherosclerosis.

Fig. 1 |. Vascular macrophage populations in mouse atherosclerotic lesions.

The adventitia of the healthy artery wall contains tissue-resident vascular macrophages. The adventitial macrophage subset is derived from embryonic precursors and is maintained by local proliferation. These tissue-resident macrophages help to regulate arterial stiffness, but their role in plaque progression is unknown. The aortic intima-resident macrophage (Mac^AIR) subset originates from monocytes that were seeded postnatally and is sustained by local proliferation during the initial phases of atherosclerosis. As disease progresses, Mac^AIR cells are replenished from classical monocytes recruited from the artery lumen and, in aged mice, from areas of neovascularization (vasa vasorum)^,. The Mac^AIR subset and cavity macrophages are likely to be the same cells. During atherosclerosis, macrophages in the neointima phagocytose apoptotic cells by efferocytosis. Monocyte-derived macrophages can become inflammatory macrophages that produce IL-1, tumour necrosis factor (TNF) and other cytokines and chemokines, which attract more classical monocytes into the intima. Decreased egress and increased retention of macrophages and monocytes in response to neuroimmune guidance cues such as netrin 1 and semaphorin 3E have been proposed to amplify the inflammatory response. Low-density lipoprotein (LDL) from the blood in the vessel lumen can enter the intimal layer, where it can become oxidized (oxLDL) or modified with aldehydes. Modified LDL is taken up by foam cells through scavenger receptors such as CD36 and SR-A. Single-cell studies have defined foam cells as the TREM2^hi macrophage subset. Endoplasmic reticulum (ER) stress of efferocytes can lead to cell death, which leads to the release of danger-associated molecular patterns (DAMPs) that are recognized by Toll-like receptors (TLRs) on inflammatory macrophages. If efferocytosis is insufficient, dead macrophages accumulate in the necrotic core. Type I interferon-inducible cells (IFNICs) are likely to produce type I interferons. IFNICs are replenished by differentiation from circulating classical monocytes. Non-classical monocytes patrol the endothelium of the blood vessel and can enter the plaque, but their further fate remains unknown. TREM2, triggering receptor expressed on myeloid cells 2.

Fig. 2 |. Adaptive immune cells in atherosclerosis.

T cell subsets encounter atherosclerosis-associated antigens in secondary lymphoid organs, where antigen-presenting cells (APCs) arriving through the lymphatics present cognate peptides on MHC class I molecules to naive CD8⁺ T cells and on MHC class II molecules to naive CD4⁺ T cells. The nature of the co-stimulatory molecules and cytokines determines T cell polarization. BCL-6⁺ T follicular helper (T_FH) cells stay in the secondary lymphoid organs and provide help to B cells in germinal centres. Other CD4⁺ T cells — T helper 1 (T_H1) cells, T_H2 cells, T_H17 cells and regulatory T (T_reg) cells — as well as CD8⁺ cytotoxic T lymphocytes (CTLs), enter the systemic circulation and home back to the plaque, where APCs initiate a recall response and trigger cytokine secretion (by CD4⁺ T_H cells) or killing (by CD8⁺ CTLs). The main cytokines produced are listed for each cell type, together with their pro-atherosclerotic effects (red) and anti-atherosclerotic effects (green). T_reg cells regulate T cell activation and responses through the production of IL-10 and transforming growth factor-β (TGFβ) and through contact-dependent mechanisms. FOXP3⁺ T_reg cells are plastic (acquiring other transcription factors in addition to FOXP3) or unstable (losing FOXP3 expression and becoming ex-T_reg cells). B cell-derived plasma cells enter the bone marrow and produce IgM or, if class-switched, IgG antibodies to atherosclerosis antigens. In the adventitia of arteries with advanced atherosclerosis, arterial tertiary lymphoid organs form, which contain germinal centres, T_FH cells and B cells that mature to antibody-secreting plasma cells. IFNγ, interferon-γ; TNF, tumour necrosis factor; VCAM1, vascular cell adhesion molecule 1; VSMC, vascular smooth muscle cell.