Plasmacytoid dendritic cells in atherosclerosis

Abstract

Atherosclerosis, a chronic inflammatory disease of the vessel wall and the underlying cause of cardiovascular disease, is initiated and maintained by innate and adaptive immunity. Accumulating evidence suggests an important contribution of autoimmune responses to this disease. Plasmacytoid dendritic cells (pDCs), a specialized cell type known to produce large amounts of type I interferons (IFNs) in response to bacterial and viral infections, have recently been revealed to play important roles in atherosclerosis. For example, the development of autoimmune complexes consisting of self-DNA and antimicrobial peptides, which trigger chronic type I IFN production by pDCs, promote early atherosclerotic lesion formation. pDCs and pDC-derived type I IFNs can also induce the maturation of conventional DCs and macrophages, and the development of autoreactive B cells and antibody production. These mechanisms, known to play a role in the pathogenesis of other autoimmune diseases such as systemic lupus erythematosus and psoriasis, may also affect the development and progression of atherosclerotic lesion formation. This review discusses emerging evidence showing a contribution of pDCs in the onset and progression of atherosclerosis.

Keywords: atherosclerosis; plasmacytoid dendritic cells; type I IFN.

Figure 1

Plasmacytoid DCs in atherosclerosis. (A) pDCs activated by nucleic acids of viral, bacterial or self-origin via TLR7 and TLR9 produce robust amounts of IFNα. This cytokine enhances the sensitivity of other antigen presenting cells by upregulation of TLR4. Furthermore, IFNα upregulates the expression of the pro-apoptotic molecule TRAIL on CD4⁺ T cells, thereby multiplying their cytotoxic potential. These TRAIL-expressing T cells have the ability to kill plaque-resident cells such as vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). IFNα activates cDCs and macrophages (MΦ) to produce effector molecules such as metalloproteinases (MMP) degrading the extracellular matrix, and proinflammatory cytokines, such as IL-12, TNFα or IL-23 (Niessner and Weyand, 2010). (B) The antimicrobial peptides LL37/Cramp secreted by infiltrating neutrophils bind self-DNA fragments released from dying cells to form aggregates of self-DNA–LL37/Cramp. These complexes activate pDCs and lead to a robust type I interferon production. Furthermore, netting neutrophils release nuclear chromatin structures riddled with antimicrobial granule proteins, and also these complexes may be strong stimulators of IFNα production by pDCs within atherosclerotic lesions. Ultimately, IFNα released by activated pDCs supports humoral immunity, e.g., by enabling B cells to undergo isotype-switching and to mature into antibody-secreting cells. Autoantibodies in turn can bind self-DNA to form autoimmune complexes that in addition trigger IFNα secretion by pDCs (Le Bon et al., 2001). (C) Modified lipids, such as oxLDL, are deposited within atherosclerotic lesions, and may be encountered by pDCs resulting in enhanced CD36 surface expression and antigen uptake by pDCs. Subsequently, pDCs can stimulate increased antigen-specific T-cell proliferation and cytokine secretion by T cells furthermore promoting inflammation. (The order of Roman numbers is not hierarchical, all stimulation scenarios described may happen simultaneously.)