The multi-functionality of CD40L and its receptor CD40 in atherosclerosis.
Disrupting the CD40-CD40L co-stimulatory pathway reduces atherosclerosis and induces a stable atherosclerotic plaque phenotype that is low in inflammation and high in fibrosis. Therefore, inhibition of the CD40-CD40L pathway is an attractive therapeutic target to reduce clinical complications of atherosclerosis. The CD40-CD40L dyad is known to interact with other co-stimulatory molecules, to activate antigen-presenting cells (APC) and to contribute to T-cell priming and B-cell isotype switching. Besides their presence on T-cells and APCs, CD40 and CD40L are also present on macrophages, endothelial cells and vascular smooth muscle cells in the plaque, where they can exert pro-atherogenic functions. Moreover, recent progress indicates the involvement of neutrophil CD40, platelet CD40L and dendritic cell CD40 in atherogenesis. Since systemic CD40-CD40L modulation compromises host defense, more targeted interventions are needed to develop superior treatment strategies for atherosclerosis. We believe that by unravelling the cell-cell CD40-CD40L interactions, inhibition of cell-type specific (signalling components of) CD40(L) that do not compromise the patient's immune system, will become possible. In this review, we highlight the cell-type specific multi-functionality of CD40-CD40L signalling in atherosclerosis.
Lievens
Dirk
D
Department of Pathology, University of Maastricht, 6229 HX Maastricht, The Netherlands.
Eijgelaar
Wouter J
WJ
Biessen
Erik A L
EA
Daemen
Mat J A P
MJ
Lutgens
Esther
E
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D001402:B-Lymphocytes / Q000502:physiology; D001792:Blood Platelets / Q000502:physiology; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000502:physiology*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000502:physiology*; D003713:Dendritic Cells / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008955:Models, Cardiovascular; D009000:Monocytes / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D009504:Neutrophils / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology
D019013:CD40 Antigens; D023201:CD40 Ligand