Besides their well-established role as the first cellular response in the coagulation cascade [95, 96], platelets are intimately involved in inflammatory reactions largely because of their direct crosstalk with leukocytes . Upon vascular injury and endothelial denudation, platelets adhere and aggregate via their contacts with the free subendothelial matrix. However, platelets also rapidly adhere to the activated vascular endothelium. Endothelial-adherent platelets promote further endothelial activation . Indeed, platelets adhere to the vascular endothelium of the carotid artery in ApoE-deficient mice before the development of advanced atherosclerotic lesions [99–101].
The interaction of platelets with both leukocytes and endothelial cells provides an important process in inflammation [97, 102]. First, platelet adhesion on endothelial cells and the release of potent inflammatory and mitogenic substances by platelets can alter the adhesive, chemotactic and proteolytic properties of endothelial cells thereby supporting the adhesion and transmigration of leukocytes to the inflamed tissue [103, 104]. Second, activated platelets release a variety of growth factors, inflammatory cytokines and chemokines into their microenvironment that can further directly stimulate leukocytes . For instance, platelets are a major source for the chemokine stromal cell-derived factor-1 (SDF-1) [105, 106], which supports leukocyte integrin activation and thereby primary adhesion of circulating leukocytes to the vascular endothelium . Third, platelets can directly interact with leukocytes; the platelet–leukocyte/monocyte aggregates have been implicated in atherosclerotic lesion formation [99, 108, 109]. The platelet receptors P-selectin, GPIb and glycoprotein IIb/IIIa contribute substantially to these inflammatory processes in inflammation and atherosclerosis [99, 108–111]. Fourth, via their direct interaction with both endothelial cells and leukocytes, platelets can serve as a bridge to promote leukocyte adhesion to the vascular wall [68, 99, 110, 112] (Fig. 1B). The mechanisms involved in the crosstalk between platelets and leukocytes are multiple. Platelet-leukocyte interactions can be mediated by both selectin-dependent and integrin-dependent adhesive interactions. In particular, P-selectin on platelets interacts with PSGL-1 on leukocytes [110, 113, 114]. A central leukocyte receptor mediating adhesion to platelets is the integrin Mac-1 [115, 116]. Mac-1 can interact with several platelets receptors. For example, the interaction between Mac-1 and glycoprotein Ib (GPIb) on platelets can mediate adhesive interactions between leukocytes and platelets [68, 115, 116]. Inhibition of the Mac-1/GPIb interaction has been implicated as a therapeutic target in several inflammatory diseases [115–119]. Another major ligand for leukocyte Mac-1 is platelet JAM-C, promoting recruitment of leukocytes and dendritic cells [67, 68]. Fibrinogen bound onto platelet glycoprotein IIb/IIIa (αIIbβ3-integrin) may also serve as a binding site for leukocyte Mac-1, thereby modulating the recruitment of leukocytes to sites of inflammation by platelets [120, 121].
The relevance of leukocyte-platelet interactions is not restricted to chronic inflammatory disease, but is important in a variety of processes in immunity, including the immune response to bacterial infections. For instance, during the course of infections microbial contents trigger immune-mediated platelet activation and thrombus formation resulting in a proinflammatory and procoagulatory state of the infected tissue [122–124]. In an in vivo model of sepsis, Clark et al. demonstrated that platelets stimulate the formation of extracellular traps by neutrophils that can engulf bacteria in the septic blood . Platelets can also contribute to cytotoxic T-lymphocyte (CTL) mediated liver immunopathology independently of their procoagulant function . In this study, platelet depletion reduced accumulation of virus specific CTLs in mouse models of acute viral hepatitis and subsequently liver damage . On the other hand, platelets and their released growth factors are important for tissue regeneration [127, 128]. Using a mouse model of liver regeneration it was shown that platelet-derived serotonin is centrally involved in the initiation of liver regeneration .