Platelets and the complement cascade in atherosclerosis

Abstract

Atherosclerosis and its late sequels are still the number one cause of death in western societies. Platelets are a driving force not only during the genesis of atherosclerosis, but especially in its late stages, as evidenced by complications such as arterial thrombosis, myocardial infarction, and ischemic stroke. Atherosclerosis is increasingly recognized as an inflammatory disease, influenced by various immune mechanisms. The complement system is part of our innate immune system, and its diverse roles in atherosclerosis have become evident over the past years. In this review we identify points of intersection between platelets and the complement system and discuss their relevance for atherosclerosis. Specifically, we will focus on roles for platelets in the onset as well as progression of the disease, a possible dual role for complement in the genesis and development of atherosclerosis, and review emerging literature revealing previously unrecognized cross-talk between platelets and the complement system and discuss its possible impact for atherosclerosis. Finally, we identify limitations of current research approaches and discuss perspectives of complement modulation in the control of the disease.

Keywords: atherosclerosis; complement system proteins; inflammation; innate immunity; platelets.

Figure 1

Upper part: Model of platelet interaction with the damaged vessel wall: exposure of subendothelial matrix after endothelial lesion leads to platelet tethering, activation and accumulation to provide sealing of the endothelial wound. Lower part: Model of platelet interaction with the endothelium. Platelets interact with the endothelium via adhesion receptors such as GPIbα and PSGL-1 promoting rolling and subsequent firm adhesion via β3 integrins. Interaction with endothelial bound chemokines such as Cx3CL1 (fractalkine) or CCL5 (Rantes) results in P-Selectin mediated recruitment of leukocytes to the vessel wall and subsequent transmigration. For both interaction with the subendothelial matix and the endothelium, major adhesion receptors expressed on platelets are listed.

Figure 2

Complement activation within the atherosclerotic plaque. TCC, terminal complement complex; C3, C3a, C4bp, different components of the complement cascade; fH, factor H.

Figure 3

Consequences of complement activation: complement interacts with inflammatory cells, may, however, also have a functional relationship with platelet activation. Via promotion of inflammation, complement contributes to the formation of the fatty streak, under distinct conditions, however, atheroprotective effects can not be excluded.