Dendritic cells in atherosclerotic disease

Abstract

Atherosclerosis has been considered a syndrome of dysregulated lipid storage until recent evidence has emphasized the critical contribution of the immune system. Dendritic cells (DC) are positioned at the interface of the innate and adaptive immune system. Recognition of danger signals in atheromas leads to DC activation. Activated DC regulate effector T cells which can kill plaque-resident cells and damage the plaque structure. Two types of DC have been identified in atherosclerotic lesions; classical myeloid DC (mDC) which mainly recognize bacterial signatures and plasmacytoid DC (pDC) which specialize in sensing viral fragments and have the unique potential of producing large amounts of type I interferon (IFN). In human atheromas, type I IFN upregulates expression of the cytotoxic molecule TRAIL which leads to apoptosis of plaque-resident cells. This review will elucidate the role of DC in atherogenesis and particularly in plaque rupture, the underlying pathophysiologic cause of myocardial infarction.

Figure 1. Recruitment of Dendritic Cells into the Atherosclerotic Plaque

DC are tethered to activated endothelium covering atherosclerotic plaques with the help of adhesion molecules including P-Selectin, E-Selectin, and VCAM-1. Production of chemokines in the atherosclerotic lesion determines which cells enter the lesion. The chemokines CCL2, CCL5, and CX₃CL1 are abundantly expressed in the lesion and build a gradient towards the lesion in the vessel wall. DC express the corresponding receptors CX₃CR1, CCR2, and CCR5 and follow the gradient towards the atheroma. Transmigration through the endothelium is associated with phenotypic changes of DC. DC = dendritic cells

Figure 2. The Role of Dendritic Cells in the Atherosclerotic Plaque

mDC are activated by exogenous and endogenous danger signals binding to TLR2 and TLR4. Activated mDC produce effector molecules such as metalloproteinases degrading the extracellular matrix. Further, they trigger the recruitment of cytotoxic T cells via production of IL-12. pDC are mainly activated by viral antigens binding to intracellular receptors such as TLR9. Activated pDC produce vast amounts of IFN-α. This cytokine enhances the sensitivity of other antigen-presenting cells by upregulation of TLR4. Furthermore, it upregulates the expression of the proapoptotic molecule TRAIL on T cells thereby multiplying their cytotoxic potential. These TRAIL-expressing T cells have the ability to kill plaque-resident cells such as activated VSMC and EC expressing the death receptor DR5. VSMC = vascular smooth muscle cells, EC = endothelial cells, mDC = myeloid dendritic cells, pDC = plasmacytoid dendritic cells, MMP = metalloproteinase, DR5 = death receptor 5, TNF-α = tumor necrosis factor-alpha