Endothelial Determinants of Dendritic Cell Adhesion and Migration

Abstract

Objective-Atherosclerosis is a chronic disease triggered by endothelial injury and sustained by inflammation. Dendritic cells (DCs) are critical for the cell-mediated arm of an immune response and are known to influence inflammatory immunity. A fundamental aspect of DC function is their capacity to adhere and migrate through vascular endothelial cells (ECs). We investigated the role of endothelial activation and dysregulation of the NO pathway on DC adhesion and migration. Methods and Results-We discovered that DC adhesion and migration are modulated by changes in endothelial function.DC adhesion and transmigration were markedly increased after exposing ECs to hypoxia, oxidized low density lipoprotein, or tumor necrosis factor-␣. Specifically, inhibition of endothelial NO synthase increased DC binding and transmigration. L-Arginine or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition partially decreased DC-EC interaction. Conclusions-The results of this study suggest that the adhesion and migration of DCs are increased by stimuli known to accelerate atherogenesis. Vice versa, augmentation of endothelial NO synthase activity prevents DC adhesion. These findings may provide insight into the inflammatory processes occurring in atherosclerosis. Because DCs control immunity, regulating DC-EC interaction may be relevant to inflammation and atherogenesis. (Arterioscler Thromb

Endothelial Nitric Oxide Synthase Activation by Tumor Necrosis Factor α Through Neutral Sphingomyelinase 2, Sphingosine Kinase 1, and Sphingosine 1 Phosphate Receptors

“…13 Sph1P and NO regulate in an inhibitory fashion key aspects of TNF-␣ signaling in the endothelium, such as apoptosis, leukocyte adhesion, and expression of adhesion molecules. 5,6,15,19,21,24,27,28 Up to now, however, the role of Sph1P and NO had been investigated separately. We have now established a link between Sph1P and NO as messengers generated within the same signaling cascade, and we have shown that this link is of biological relevance.…”

Thematic review series: The Immune System and Atherogenesis. The unusual suspects:an overview ofthe minor leukocyte populations in atherosclerosis

“…Monocyte precursors of macrophages and dendritic cells are also recruited to the growing plaque by the activated endothelium throughout atherogenesis (69). Dendritic cells have been identified in the atherosclerotic plaques of both humans and mice by immunohistochemical and PCR-based approaches, implicating them in the pathogenesis of the disease (70)(71)(72).…”

High Ratio of Myeloid Dendritic Cells to Plasmacytoid Dendritic Cells in Blood of Patients With Acute Coronary Syndrome

“…13,20 Previous studies also showed the recruitment of circulating mDC precursors into unstable atheroma and their crucial involvement in the (auto)immune mechanisms of atherosclerosis, as well as oxidized lowdensity lipoprotein promoting the maturation of mDCs and thus enabling T-cells activation in vitro. [21][22][23] Yilmaz et al suggested that the increased recruitment of mDCs into unstable plaques and increased peripheral neutrophils and lymphocytes in patients with ACS might be responsible for decreased peripheral mDCs and relative lower percentage of mDCs. 13 We found that serum IL-12 levels associated with mDCs tended to be higher in the ACS group compared with those in the SAP group and controls.…”