Innate and adaptive immunity in atherosclerosis

Abstract

Atherosclerosis, a chronic inflammatory disorder, involves both the innate and adaptive arms of the immune response that mediate the initiation, progression, and ultimate thrombotic complications of atherosclerosis. Most fatal thromboses, which may manifest as acute myocardial infarction or ischemic stroke, result from frank rupture or superficial erosion of the fibrous cap overlying the atheroma, processes that occur in inflammatorily active, rupture-prone plaques. Appreciation of the inflammatory character of atherosclerosis has led to the application of C-reactive protein as a biomarker of cardiovascular risk and the characterization of the anti-inflammatory and immunomodulatory actions of the statin class of drugs. An improved understanding of the pathobiology of atherosclerosis and further studies of its immune mechanisms provide avenues for the development of future strategies directed toward better risk stratification of patients as well as the identification of novel anti-inflammatory therapies. This review retraces leukocyte subsets involved in innate and adaptive immunity and their contributions to atherogenesis.

Figures

Figure 1. Leukocytes and platelets release mediators that control inflammation in atherosclerotic plaques and determine lesion fate

Abbreviations: TH1 T Cell; T helper 1 T cell, Treg; Regulatory T Cell, ROS; reactive oxygen species, IFN-γ; interferon-γ, TNF-α; tumor necrosis factor-α, IL; interleukin, TGF-β; transforming growth factor-β.

Figure 1. Leukocytes and platelets release mediators that control inflammation in atherosclerotic plaques and determine lesion fate

Abbreviations: TH1 T Cell; T helper 1 T cell, Treg; Regulatory T Cell, ROS; reactive oxygen species, IFN-γ; interferon-γ, TNF-α; tumor necrosis factor-α, IL; interleukin, TGF-β; transforming growth factor-β.

Figure 2. TH1 cells and macrophages promote atherosclerosis progression

TH1-biased T lymphocytes (lower left) express IFN-γ and CD40L within plaques. IFN-γ inhibits the de novo production of collagen in response to TGF-β and PDGF by vascular smooth muscle cells (middle left). In parallel, CD40L induces the synthesis and release of proteases by macrophages (center), including the interstitial collagenases MMP-1, MMP-8, and MMP-13, which mediate the initial proteolytic attack of intact collagen fibrils. In addition, CD40L also simulates the production of the gelatinases MMP-2 and MMP-9 as well as other proteases that continue the proteolytic degradation of collagen fibrils. These combined effects orchestrated by TH1 cells and macrophages weaken the fibrous cap covering the atherosclerotic plaque — which owes its biomechanical strength to interstitial collagen (types I and III) fibrils — and render the lesion rupture-prone. Abbreviations: CD40L; CD40 Ligand, IFN-γ; interferon-γ, MMP; matrix metalloproteinase, PDGF; platelet-derived growth factor, TGF-β; transforming growth factor-β. (Figure reproduced with kind permission of Springer Science and Business Media .)

Figure 3. Dendritic cells express co-stimulatory and co-inhibitory molecules involved in T cell activation

Dendritic cells (DCs) deliver co-stimulatory (denoted by a (+) sign) and co-inhibitory (denoted by a (-) sign) signals to T cells through molecules belonging to the B-7 or TNF family. In the B-7 family, co-stimulatory molecules include CD80 (B7-1), CD86 (B7-2), and ICOS-L, and co-inhibitory molecules include PD-L1, PD-L2. T cells can render a co-stimulatory signal delivered by CD80 or CD86 co-inhibitory by replacing the CD28 receptor with CTLA-4. In the TNF family, co-stimulatory molecules include OX40-L and CD137-L. T cells also activate DCs by CD40-L, which increases DC expression of CD80 and CD86. Abbreviations: CTLA-4; cytotoxic T-lymphocyte antigen 4, ICOS; inducible co-stimulatory molecule, ICOS-L; inducible co-stimulatory molecule-ligand, PD-L1; programmed death-ligand 1, PD-1; programmed death-1, TNF; tumor necrosis factor.