Platelets in Skin Autoimmune Diseases

Abstract

Systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and small vessel vasculitis are three autoimmune diseases frequently manifested in the skin. They share common pathogenic features, including production of autoantibodies, loss of tolerance to self-antigens, tissue necrosis and fibrosis, vasculopathy and activation of the coagulation system. Platelets occupy a central part within the coagulation cascade and are well-recognized for their hemostatic role. However, recent cumulative evidence implicates their additional and multifaceted immunoregulatory functions. Platelets express immune receptors and they store growth factors, cytokines, and chemokines in their granules enabling a significant contribution to inflammation. A plethora of activating triggers such as damage associated molecular patterns (DAMPs) released from damaged endothelial cells, immune complexes, or complement effector molecules can mediate platelet activation. Activated platelets further foster an inflammatory environment and the crosstalk with the endothelium and leukocytes by the release of immunoactive molecules and microparticles. Further insight into the pathogenic implications of platelet activation will pave the way for new therapeutic strategies targeting autoimmune diseases. In this review, we discuss the inflammatory functions of platelets and their mechanistic contribution to the pathophysiology of SSc, ANCA associated small vessel vasculitis and other autoimmune diseases affecting the skin.

Keywords: SLE; SSc; autoimmune disease; complement; endothelial cell; neutrophil; platelets; vasculitis.

Figure 1

Schematic overview of distinct molecules that tune the function of platelets in autoimmune diseases. Relevant molecules has been categorized into platelet activators, soluble factors released from platelets upon activation, surface receptors that mediate the interaction with other cells and receptors that trigger platelet adhesion and activation.

Figure 2

Platelet activation and subsequent effects in SLE. ICs and DAMPs (e.g., HMGB1 or S100A8/9), both enriched in the blood of SLE patients, activate platelets through binding to platelet surface receptors FcγRIIA and TLRs. ICs further induce the complement system activation leading to the deposition of complement fragments (e.g., C1q,C4d, MAC) on the platelet surface which in turn further potentiates platelet activation. Activated platelets release their contents such as IL-1β, sCD40L, and serotonin. These factors mediate the up-regulation of adhesion molecules (e.g., E-selectin, VCAM-1, and ICAM-1) on endothelial cells, promoting the adhesion of immune cells. In addition, sCD40L and serotonin can stimulate the release of VWF from endothelial cells, but also support B cell and T cell activation. VWF mediated trapping and activation of platelets initiate coagulation which may further foster the activity of the complement system building a positive feedback loop.

Figure 3

The role of platelets in SSc pathophysiology. Ischemia-reperfusion injury associated endothelial cell damage induces platelet activation. Similar to SLE, the presence of ICs could promote hypersensitivity of platelets and complement activation. Activated platelets release their profibrotic mediators such as TGF-β, serotonin and PDGF, and these factors stimulate connective tissue fibroblasts proliferation and increase collagen production. In addition, both HMGB1 released from platelets and complement activation can support NET formation and ROS release, which further mediates vascular endothelial dysfunction. Apart from NETs, platelets derived PF4 activates endothelial cells and induces SSc associated vascular damage. Activated platelets also release sCD40L to active B cells through CD40 signaling, which leads to B cell auto-antibody production. Moreover, sCD40L and serotonin can promote the maturation of myeloid DCs, followed by IFN production and further B cell activation.

Figure 4

Platelets involvement in the pathogenesis of AAVs. Neutrophils play a crucial role in the development of AAVs. Platelet receptors CD40L and P-selectin enable the interaction with neutrophils promoting ROS generation and NET formation. ROS and NETs are toxic to the endothelium and can lead to VWF release and vascular injury. VWF is well-known to mediate platelets adhesion and aggregation. Similar to neutrophils, sCD40L-CD40 can also mediate platelet -endothelial cell interaction, which can enhance the expression of endothelial cell adhesion proteins (e.g., E-selectin, VCAM-1, and ICAM-1). C5a, a chemoattractant anaphylatoxin, can directly attract and activate neutrophils promoting the exposure of tissue factor. Tissue factor initiates the plasmatic coagulation which culminates in the generation of thrombin. Thrombin is able to further activate platelets and endothelial cells through PAR signaling pathway, followed by platelet degranulation and VWF release. In addition, C5a can also directly active endothelial cells accelerating vascular injury.

Figure 5

Platelets as therapeutic targets in skin autoimmune disease. Several treatments that interfere with the pathophysiological activity of platelets in skin autoimmune diseases have been proposed. HCQ inhibits platelet aggregation and degranulation. Clopidogrel is a P2Y12 receptor inhibitor preventing the release of platelet derived sCD40L and P-selectin. Dapirolizumab is a monoclonal antibody specifically blocking sCD40L functions. Statins are supposed to affect the thrombotic activities of platelets and to decrease the plasma levels of sCD40L.