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Endothelial determinants of dendritic cell adhesion and migration: new implications for vascular diseases
Michael Weis1, Christoph L Schlichting, Edgar G Engleman
1Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif, USA. miweis@med.uni-muenchen.de
Insights
Dendritic cell (DC) adhesion and migration increase with stimuli promoting atherosclerosis. Enhancing endothelial nitric oxide synthase (eNOS) activity reduces DC interaction with endothelial cells (ECs), potentially mitigating inflammatory processes.
Area of Science:
- Immunology
- Vascular Biology
- Atherosclerosis Research
Background:
- Atherosclerosis is a chronic inflammatory disease initiated by endothelial injury.
- Dendritic cells (DCs) are key immune cells influencing inflammatory responses.
- DC adhesion and migration through endothelial cells (ECs) are crucial for immune surveillance and inflammation.
Purpose of the Study:
- To investigate the impact of endothelial activation on DC adhesion and migration.
- To explore the role of the nitric oxide (NO) pathway in regulating DC-EC interactions.
Main Methods:
- Endothelial cells (ECs) were exposed to various stimuli (hypoxia, oxidized LDL, TNF-alpha).
- Endothelial NO synthase (eNOS) activity was modulated using inhibitors and substrates.
- DC adhesion and transmigration across EC monolayers were quantified.
Main Results:
- DC adhesion and migration were significantly increased by hypoxia, oxidized LDL, and TNF-alpha.
- Inhibition of eNOS enhanced DC adhesion and transmigration.
- L-arginine supplementation and statin treatment partially reduced DC-EC interactions.
Conclusions:
- Stimuli that promote atherosclerosis enhance DC adhesion and migration.
- Augmenting eNOS activity inhibits DC adhesion, suggesting a protective role.
- Modulating DC-EC interactions may offer therapeutic strategies for atherosclerosis and inflammation.
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-alpha. 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.