Atherosclerosis takes a huge toll on our society. It is the leading cause of morbidity and mortality in the Western world, and growing incidence of atherosclerosis-related diseases has also been recently observed in developing countries [
Dendritic cells (DCs) constitute a family of professional antigen-presenting cells that have the unique ability to induce primary T-cell responses. Moreover, they are not only essential in launching immune reactions against harmful antigens, but also in maintaining immune tolerance [
As illustrated in Figure
Schematic presentation of life cycle of DCs.
The present review is aimed at summarizing current knowledge of the role of DCs in the pathogenesis of human atherosclerosis: from circulating DC precursors in patients with coronary artery disease (CAD) to DCs found in human atherosclerotic lesions. Technical challenges and open questions in this research field are discussed in detail.
Two main DC precursor subtypes can be identified in human blood: myeloid (m)DCs and plasmacytoid (p)DCs. As DC precursors they are relatively immature and express only low levels of adhesion and costimulatory molecules—at least in physiological conditions [
Finally, a small (0.02% of leukocytes) third population of blood DCs expressing CD11c, and BDCA-3 (= CD141) but not BDCA-1, CD123 and BDCA-2 can be distinguished [
In 2006 we reported for the first time a decrease in circulating DC precursors (BDCA-1+ mDCs, BDCA-2+ pDCs) in patients with coronary artery disease (CAD), the clinical manifestation of atherosclerosis [
Subsequently, we investigated whether the decline of blood DCs in CAD patients was related to the number of diseased vessels (one- versus three-vessel disease) or type (stable versus unstable angina pectoris) of CAD [
Surprisingly, Shi et al. [
At the moment the mechanisms responsible for the decline of blood DCs in atherosclerosis are still unclear. Different possibilities are discussed below and summarized in Figure
Possible mechanisms responsible for the decline of blood DCs in atherosclerosis.
Decreased production or release from the bone marrow could result in reduced blood DC precursor numbers. As discussed above, DCs are also necessary for induction of tolerance against harmless antigens [
Another explanation for the decreased DC numbers could be the result of increased turnover, that is, decreased survival or production versus apoptosis rates. Atherosclerosis is a chronic disease, evolving over several decades with inflammatory reactions taking place from the earlier stages. It is plausible that in the end as symptoms emerge and the exposure to (new) antigens—derived from stressed and dying cells, lipid, or protein modifications due to oxidative stress in the plaque—increases, the immune system’s “reserve pool” has become exhausted. For instance it was demonstrated that oxidized low-density lipoprotein, one of the main antigens present in plaques and in the circulation of atherosclerotic patients, may cause increased apoptosis of DCs [
Activation of blood DCs by factors in the circulation (e.g., oxLDL) could account for diminished blood DC numbers by reducing the expression of precursor markers. Indeed, it has been described that pDC maturation results in complete BDCA-2 downregulation [
Though several studies investigated numbers of subsets of DCs in the circulation of CAD patients, very little additional information is available on the status of maturation and activation in circulating DCs. It is possible that in inflammatory conditions systemic activation occurs in the blood and this could lead to increased extravasation or apoptosis of blood DCs. Interestingly, inverse associations of circulating mDCs, pDCs (and total DCs) were found with blood markers of inflammation: CRP and IL-6 [
Yilmaz et al. assessed the activation status of blood DC precursors and reported a weak expression of costimulatory molecules CD40 and CD86 on circulating BDCA-1+ mDCs or BDCA-2+ pDCs [
As blood DC precursors from CAD patients remained fairly immature, we investigated their capability to achieve maturation. Therefore, we incubated whole blood samples with TLR ligands
Finally, as monocytes can serve as precursors for DCs in peripheral tissues [
Cardiovascular disease-related medication, taken by CAD patients, might influence numbers, phenotype, or function of blood DCs in atherosclerosis. Indeed, several
Kofler et al. demonstrated that
Studies on the effects of
Also angiotensin-converting enzyme-
If these
In a recent study, we analyzed the effect of medication by including “control patients,” that is, patients with chest pain and suspected CAD, who appeared to have coronary arteries with less than 50% stenosis, instead of healthy volunteers [
An attractive explanation for decreased circulating DC numbers might be increased recruitment of DCs into the vessel wall or lymphoid organs. Indeed it has been mentioned that DC numbers of lymph nodes attached to atherosclerotic wall segments exceed those in lymph nodes attached to nonatherosclerotic arteries [
The presence of DCs in human arteries was first described by Bobryshev and Lord 1995 [
Immunohistochemical markers to identify DCs in human plaques.
Marker | DC type | References | Pitfalls | References |
---|---|---|---|---|
Fascin (p55) | Immature/mature DCs; DC specific in early plaque stages | [ | Capillary ECs, migrating vascular cells in plaque shoulders and advanced plaques | [ |
S100 (S100B and weakly S100A1) | Immature/mature DCs; DC specific in normal intima and all plaque stages | [ | Nerve bundles and twigs in adventitia | [ |
Langerin | Selectively expressed on the surface and in Birbeck granules of Langerhans cells | [ | Very few cells | [ |
CD1a | Mature DCs | [ | CD14+, CD68+ foam cells | [ |
CD83 | Mature DCs | [ | Aspecific staining due to signal amplification? Activated T cells and monocytes? | [ |
DC-SIGN (CD209) | Immature/mature DCs | [ | Macrophages | [ |
DC-LAMP (CD208) | Mature DCs | [ | ||
BDCA-1 (CD1c) | mDC | [ | B cells | [ |
BDCA-2 (CD303) | pDC precursor | [ | [ | |
CD11c | mDCs | [ | CD14+ monocytes and CD68+ macrophages | [ |
CD123 | pDCs | [ | ECs, microvessels in advanced plaques, and plaque shoulders | [ |
DC: dendritic cells, EC: endothelial cell, pDC: plasmacytoid DC, mDC: myeloid DC.
Examples of useful plaque DC markers: S100 (a), fascin (b, c), BDCA-1 (d) and BDCA-2 (e). Arrows indicate DCs. Arrowheads show fascin+ neovessels. * indicates lumen of microvessel.
At first, it became clear that
Secondly, false-positive results, resulting from
Thirdly
Finally, there is
Interestingly, both mDC and pDC precursor markers were found in carotid atherosclerotic plaques, although less BDCA-2+ (pDC marker) cells were present [
The demonstration of BDCA-2+ and BDCA-1+ cells in human plaques strongly suggests that blood DCs are recruited into advanced lesions. This is further strengthened by the observation that both BDCA+ subsets were predominantly found around microvessels [
S100+ and fascin+ DCs are found in normal arteries and in all successive stages of atherosclerotic lesions [
Though the presence of S100 in normal intimal thickenings is limited, numbers of S100+ cells increase successively from intimal thickening, via pathological intimal thickening, fibrous cap atheroma and finally complicated plaques [
The report on abundant presence of CD83+ cells in plaque shoulders [
Different explanations for increased DC numbers in atherosclerotic lesions are discussed below and summarized in Figure
Possible mechanisms responsible for the increase of vascular DCs in atherosclerosis.
At first and in view of the many reports on diminished blood DCs in patients with established atherosclerosis, one likely explanation is increased invasion of DC precursors from the blood into the arterial lesions. This hypothesis is strengthened by the present markers of pDCs and mDCs around neovessels. Future studies will have to determine whether a link exists not only between plaque type and numbers of lesional DCs, but also with blood DC counts. It is possible that, the clinical division in stable or unstable, was not refined enough to detect this correlation. Ideally, DCs have to be investigated in peripheral blood and plaque samples of the same patient, or in an animal model of experimental atherosclerosis, with fluorescence labeling of DCs, to characterize their origin, to postulate an increased influx of blood DC precursors as a mechanism for increased DC numbers in atherosclerotic plaques. Direct information on the stimuli regulating DC migration is scarce. However, it is known that effective mDC as well as pDC chemokine factors (CCL2, CCL5, and CXCL-12) are elevated in patients with atherosclerosis [
In spite of these indications that blood DC precursors might account for increased plaque DC numbers, the origin of immature/mature (S100+ or fascin+) DCs remains unclear [
It was recently suggested that the accumulation of DCs in plaques could be the result of defective emigration of DCs from the lesions to draining lymph nodes [
This review summarizes the current understanding of the possible role of DCs in the pathogenesis of human atherosclerosis. Concerning the early stages of DC differentiation, that is, circulating DC precursors, it is now unambiguous that they are significantly decreased in CAD patients, irrespective of the blood DC markers used for enumeration. Exact mechanisms responsible for their decline remain unclear. However, there are indications pointing to impaired differentiation from bone marrow progenitors, and to activation and subsequent recruitment to inflammatory sites, such as atherosclerotic plaques. Indeed, both mDCs and pDCs can be found in human plaques, particularly around neovessels in areas with angiogenesis. Furthermore, DC counts in the intima of arteries increase with evolving plaque stages, and activated DCs are seen in close relationship with lesional T cells. To which extent these interactions between DCs and T cells result in progression or dampening of atherosclerosis is, however, not yet clear. Interestingly, it has been demonstrated in mice that decreased accumulation of DCs in the arterial intima can lead to attenuated plaque progression [
E. A. Van Vré and I. V. Brussel contributed equally to the paper.