5 The Platelet as an Immunomodulator: The Old Thespian with New Roles in Atherosclerosis, Sepsis and Autoimmune Disease (original) (raw)

Inflammation, Chronic Diseases and Cancer-Cell and Molecular Biology, Immunology and Clinical Bases 98 inflammatory diseases such as sepsis, rheumatoid arthritis, and acute lung injury set the stage for modification of the thespian paradigm. One that helps us complete the continuum from coagulation to inflammation and back to coagulation again. Here we propose to name this field of study "Immunohemostasis". No better model to appreciate the crosstalk between coagulation and inflammation than atherosclerosis. 2. Platelets have a role early in the development of atherosclerosis Although platelets are not solely responsible for the development of atherosclerosis, their contribution to the inception of the vascular lesion, up until to atherothrombosis-its most critical consequence-is conceptually best understood as a model of inflammation. This is somewhat amusingly explained by Rudolf Virchow on a footnote in, Cellular Pathology (1865), "Suppose three people were sitting quietly on a bench, and suddenly a stone came and injured one of them, the others would be excited, not only by the sudden appearance of the stone, but also by the injury done to their companion, to whose help they would feel bound to hasten. Here the stone would be the irritant, the injury the irritament, the help an expression of the irritation called forth in the bystanders". Following Dr. Virchow's thought process, modern science not only has documented many different stones but also acknowledges that at times, these bystanders can hasten the irritament (inflammatory stimulus), therefore as we will understand an overzealous and excited bystander could prove to be, vessel hardening. If we look at atherosclerosis as a model of inflammatory disease, platelet adhesion could similarly be regarded as a model of platelet induced disease (Langer & Gawaz, 2008). Atherogenesis is influenced by platelets that adhere to activated vascular endothelial cells and feed chemotactic mediators to adjoining cells. Although the underlying mechanism of atherosclerosis is attributed to endothelial impairment due to insults from genetic and environmental factors (Lusis, 2000), it needs platelet firm adhesion to the endothelium for inception of the atheromatous plaque (Spagnoli et al., 2007). Genetic and environmental factors that trigger injurious events, which include the formation of reactive oxygen species, reduce the bioavailability of nitric oxide (Lowenstein et al., 2005). Then the nondenuded, but aggravated endothelium fails to inhibit control over Weibel-Palade body exocytosis translocating P-selectin and von Willebrand Factor (vWF) from within the granules to the outer cellular surface (Wagner & Frenette, 2008). These two proteins allow the adhesion of platelets to the vascular endothelium in a multistep process. First platelets are tethered to the vascular wall with assistance by endothelial selectins. Platelets then roll on the vascular endothelial cells (Polgar et al., 2005). Depending on further activation of the endothelial cell and expression of endothelial integrins, the platelet adheres firmly to the vascular wall (May et al., 2008), or in the absence of further endothelial activation, the platelet, disengages from the vessel wall and returns to circulation (White, 2007). Remarkably this can occur due to the fact that platelet activation is not required for platelet rolling (Harrison, 2005). In contrast, experimental models of mice infused with activated platelets also stimulate Weibel-Palade body exocytosis, promoting the development of atherosclerosis which is attributed to platelet P-selectin-mediated delivery of platelet-derived proinflammatory factors to monocytes/leukocytes and the vessel wall (Delvaeye & Conway, 2009).