Platelets and Immune Responses During Thromboinflammation

Abstract

Besides mediating hemostatic functions, platelets are increasingly recognized as important players of inflammation. Data from experiments in mice and men revealed various intersection points between thrombosis, hemostasis, and inflammation, which are addressed and discussed in this review in detail. One such example is the intrinsic coagulation cascade that is initiated after platelet activation thereby further propagating and re-enforcing wound healing or thrombus formation but also contributing to the pathophysiology of severe diseases. FXII of the intrinsic pathway connects platelet activation with the coagulation cascade during immune reactions. It can activate the contact system thereby either creating an inflammatory state or accelerating inflammation. Recent insights into platelet biology could show that platelets are equipped with complement receptors. Platelets are important for tissue remodeling after injury has been inflicted to the endothelial barrier and to the subendothelial tissue. Thus, platelets are increasingly recognized as more than just cells relevant for bleeding arrest. Future insights into platelet biology are to be expected. This research will potentially offer novel opportunities for therapeutic intervention in diseases featuring platelet abundance.

Keywords: EAE; complement; infection; inflammation; innate immunity; platelets; stroke; tissue remodeling.

Figure 1

The role of platelets for tissue remodeling, apoptosis and angiogenesis. Platelets can have an influence on tissue remodeling under different pathological and physiological conditions. For tissue remodeling as well as apoptosis and angiogenesis, platelets are equipped with a multitude of receptors. HGF and SDF-1, for example, are of relevance in tissue fibrosis. In addition, platelets can release a multitude of proteins. Among these are proteins with strong pro- or antiangiogenic effects. PF4 and endostatin are known to inhibit angiogenesis. In contrast, VEGF, which platelets can release as well, strongly increases angiogenesis. Since platelets are transported within the blood-stream they can reach almost all organs and tissues thereby even influencing processes associated with inflammation in the brain and systemic diseases like atherosclerosis. In addition, platelet mediated apoptosis through FasL on the platelet surface has been reported in the brain. VEGF, vascular endothelial growth factor; PF4, platelet factor 4; SDF-1, stromal derived factor; HGF, hepatocyte growth factor; JAM-C, junctional adhesion molecule C; IL1β, Interleukin 1β; FasL, Fas-ligand; ADP, adenosine diphosphate; FXII, coagulation factor XII.

Figure 2

Mechanisms of interactions between platelets and their microenvironment. Platelets were first recognized to be important for thrombosis and hemostasis after vessel injury has happened. In addition, there is accumulating evidence that platelet function goes beyond thrombosis and hemostasis. Platelets interact with a multitude of cells and proteins. Among these are receptors and proteins modulating thrombosis/hemostasis, e.g., GPIbα, GPIIb/IIIa, GPVI, and polyphosphates. In addition, platelets modulate inflammation, e.g., through C3aR, JAM-C, PSGL-1, P-selectin, CXCR4. GPIbα, glycoprotein Ibα; GPIIb/IIIa, glycoprotein IIb/IIIa; GPVI, glycoprotein VI; C3AR, receptor for complement factor 3; JAM-C, junctional adhesion molecule C; CXCR4, C-X-C-chemokine receptor type 4.

Figure 3

Mechanisms of activated platelets after organ transplantation Platelets may be activated before, during and after allogeneic organ transplantation. Direct interaction with the immune system may occur via simultaneous P-selectin and CD40 binding to leukocytes. Non-nucleated platelets contain dense granules with serotonin, ADP and α-granules with pro-inflammatory cytokines, such as RANTES, TNFα, PDGF, and VWF. Surface receptors including glycoprotein receptors lead to collagen binding, VWF and fibrogen activation. Activated leukocytes adhere to the endothelium of transplanted grafts, migrate and release growth factors and pro-inflammatory cytokines finally leading to smooth muscle cell proliferation, collagen deposition and further leukocyte activation.