Dendritic cells in cardiovascular diseases: epiphenomenon, contributor, or therapeutic opportunity.

C ardiovascular diseases (CVDs) are one of the leading causes of mortality worldwide. 1 It has been so for decades, notwithstanding a wide array of – mostly preventive – treatment modalities targeting known risk factors, such as hyperlipidemia, type 2 diabetes mellitus, hypertension, or obesity. Recent technical and conceptual advances have unveiled important contributions of the immune system in the pathophysiology of a variety of CVDs such as atherosclerosis, ischemic stroke, chronic heart failure, and other myocardial conditions like myocardial ischemia and reperfusion, viral myocarditis, and cardiac transplantation. 2–4 In many of these disorders, so-called danger-associated molecular patterns (DAMPs), released from necrotic tissue and dying cells, can lead to the activation of certain immune cell populations such as monocytes/ macrophages, granulocytes, and T cells, thus aggravating ongoing inflammatory processes at the lesion site. Dendritic cells (DCs) are key modulators of immunity, pivotal in directing innate and adaptive immune responses against microbial, viral, but also modified self-antigens present at the sites of injury. Given the tissue trauma underlying various CVDs, it is not surprising that recent observations have allocated a regulatory role for DCs in CVD-associated immune responses. Interestingly, nondiseased arteries of young individuals were seen to host a network of resident vascular DCs (CD1a + S100 + lag + CD31 − CD83 − CD86 −), 5 representing a phenotype related to Langerhans cells in the skin. In agreement , monocyte-derived CD11c + CD68 + dendritic cells could be detected in the atherosclerosis-prone lesser curvature and aortic sinus in inbred atherosclerosis-susceptible (C57Bl/6), but not resistant mouse strains (balb/c). 6 Murine vascular resident DCs express an immature phenotype with low expression of costimulatory molecules, and are present in the subendo-thelial space with occasional probing into the vascular lumen. DCs have also been observed in human heart and in cardiac valves of healthy C57BL/6 mice. 7 It is assumed that these immature, resident DCs contribute to the maintenance of vas-cular homeostasis and tolerance by scanning their microen-vironment for self-and non–self-antigens. Indeed, Choi and coworkers 8 were able to show that resident DCs, isolated from the aorta and the valves of wild-type mice, have the capacity to present antigens to CD8 + T cells in vitro and in vivo, indicating that they are fully functional in eliciting a T-cell response. In diseased vessels, the heart and brain of human CVD patients, but also in the circulation, DC subset numbers were reported to be modified, …