Immune and inflammatory mechanisms of atherosclerosis (*)

Abstract

Atherosclerosis is an inflammatory disease of the wall of large- and medium-sized arteries that is precipitated by elevated levels of low-density lipoprotein (LDL) cholesterol in the blood. Although dendritic cells (DCs) and lymphocytes are found in the adventitia of normal arteries, their number is greatly expanded and their distribution changed in human and mouse atherosclerotic arteries. Macrophages, DCs, foam cells, lymphocytes, and other inflammatory cells are found in the intimal atherosclerotic lesions. Beneath these lesions, adventitial leukocytes organize in clusters that resemble tertiary lymphoid tissues. Experimental interventions can reduce the number of available blood monocytes, from which macrophages and most DCs and foam cells are derived, and reduce atherosclerotic lesion burden without altering blood lipids. Under proatherogenic conditions, nitric oxide production from endothelial cells is reduced and the burden of reactive oxygen species (ROS) and advanced glycation end products (AGE) is increased. Incapacitating ROS-generating NADPH oxidase or the receptor for AGE (RAGE) has beneficial effects. Targeting inflammatory adhesion molecules also reduces atherosclerosis. Conversely, removing or blocking IL-10 or TGF-beta accelerates atherosclerosis. Regulatory T cells and B1 cells secreting natural antibodies are atheroprotective. This review summarizes our current understanding of inflammatory and immune mechanisms in atherosclerosis.

Conflict of interest statement

Disclosure Statement: The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

Figures

Figure 1

Immune and inflammatory cells in atherosclerosis. Atherosclerotic lesion (foreground, bottom) and relatively unaffected areas. The endothelial cells above the lesion are polygonal in shape (cobblestone), whereas normal endothelial cells are aligned with the direction of flow. The normal intima is so thin as to be invisible at this level of resolution, but it is greatly expanded in the lesion area, where it contains vascular dendritic cells, macrophages, and foam cells (blue) as well as occasional T lymphocytes (gray). The foam cells surround the necrotic core (brown), which is thought to be composed of foam cells that have undergone secondary necrosis. The normal media is populated by smooth muscle cells that are organized by several elastic laminae (magenta lines). These laminae move apart as the smooth muscle cells assume a secretory phenotype and may form foam cells. Myeloid cells (blue) invade the media in the lesion area. The normal adventitia is populated by sparse T cells (gray), B cells (green), and other lymphocytes (brown) as well as vascular DCs (blue). In the lesion area (bottom), the lymphocytes organize into tertiary lymphoid structures, containing high endothelial venules and other vessels. The angiogenic process eventually leads to neovessels invading the intima, a process that is thought to destabilize plaque and precipitate rupture events. The normal adventitia contains some microvessels (vasa vasorum, in background) that do not penetrate the elastic lamina separating the media from the adventitia.

Figure 2

Monocyte recruitment to the atherosclerosis-prone vessel wall. Monocytes use an overlapping network of adhesion molecules and chemokine receptors to enter the artery wall. P-selectin supports rolling and monocyte-platelet interactions. Monocyte α4β1 integrin interacting with endothelial VCAM-1 reduces rolling velocity and leads to firm adhesion. Surface-immobilized chemokines including CXCL1, CXCL2, CXCL4, CCL5, and others can activate monocytes as they roll by, leading to increased adhesiveness of α4β1 integrin through inside-out signaling and receptor clustering. Ly6Chigh monocytes use CCR2, CX3CR1, and CCR5 to migrate to aortas, whereas Ly6Clow monocytes use CCR5. L-selectin, interacting with an unknown ligand, and CXCR6, likely interacting with CXCL16, are partially responsible for lymphocyte recruitment, likely from vasa vasorum and under lesions from high endothelial venules.

Figure 3

Macrophage functions. Macrophages express scavenger receptors (SRs), TLRs, and other receptors for pathogen-associated molecular patterns (PAMPs). Engagement of these receptors results in release of proinflammatory cytokines IL-1, IL-6, IL-12, IL-15, IL-18, TNF-α, and MIF, as well as anti-inflammatory IL-10 and TGF-β. Vascular endothelial growth factor (VEGF) promotes angiogenesis.

Figure 4

Interactions between DCs and T cells. DCs may present possible atherosclerosis antigens (possibly derived from HSP-60 and oxLDL) to T cells in the context of costimulatory molecules like CD40, OX40L, CD80, and CD86, eliciting T cell differentiation and proliferation. Although a Th1-biased response is documented in atherosclerosis, there is also a significant body of evidence suggesting a possible role for Th2 cells in mature lesions. Whether newly discovered Th17 cells also play a role remains to be investigated. Treg cells have antiatherogenic effects and play a protective role against atherosclerosis, mainly by secreting IL-10 and TGF-β.

Figure 5

Egress of macrophages and DCs from the arterial wall. The factors that control retention of macrophages and DCs in atherosclerotic vessels are not well defined, but sphingosine-1-phosphate (S1P) may have a role in this process. CCR7 expression is necessary for the exit of DCs and macrophages from atherosclerotic plaques.

Figure 6

NK cells. Activated NK cells produce IFN-γ, which promotes a Th1 response, and release perforin and granzymes, which causes apoptosis in target cells.

Figure 7

NKT cells. Dendritic cells present glycolipids on CD1 molecules to NKT cells expressing Vα14 TCR. This results in the production of the Th1 cytokines IFN-γ and TNF-α, the Th2 cytokines IL-4, IL-5, and IL-13, and the anti-inflammatory cytokine IL-10 by the NKT cells and production of IL-12 by the dendritic cells.

Figure 8

Mast cells. Interactions of mast cells with DCs may promote release of proatherogenic TNF-α, INF-γ, and IL-6, a broad spectrum of proteases, the 5-lipoxygenase product leukotriene (LT) B4, and GM-CSF. Mast cells may direct the development of Th1 or Th2 responses.

Figure 9

B cells. The B1 subset of B cells is independent of T cell help and produces IgM natural antibodies that appear to have atheroprotective functions. They may be triggered by foreign or self-antigens through their B cell receptor (BCR). Th1-dependent B2 cells produce IgG2a and IgG1. B cells also produce IL-10.

Figure 10

Neutrophils. Neutrophils, although rare in mature atherosclerotic lesions, interact with the endothelium covering atherosclerotic lesions and may release reactive oxygen species (ROS), myeloperoxidase (MPO), proteases, and the chemokines CXCL1 and CXCL8.

Figure 11

Platelets. Activated platelets release proinflammatory IL-1β, CD40L, CXCL12, CXCL4, and CCL5 as well as anti-inflammatory TGF-β. Through P-selectin binding to PSGL-1, platelets interact with monocytes.