Platelet signaling in immune landscape: comprehensive mechanism and clinical therapy

Figures

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  Fig. 1. Illustration of platelets in different conditions and diseases. In stable homeostasis, platelets perform a multitude of physiological functions by preserving vascular integrity, maintaining the balance of the immune system, and other conditions. Platelets preserve vascular integrity by influencing blood hemostasis, wound healing, lymphatic integrity, vasoconstriction, angiogenesis and plasma homeostasis. Platelets take part in the immune response by regulating inflammatory reactions, influencing immune cell extravasation, interacting with innate and adaptive immune cells, regulating antimicrobial responses and controlling cytokine/chemokine release. Besides, platelets also perform other physiological functions such as absorbing or transmitting mRNA or miRNA to other cells. In disturbed homeostasis, platelets affect the pathogenesis of several disease states, mainly including thrombotic disorders, malignancies, infections and other related diseases. Platelets affect thrombotic disorders mainly including atherosclerosis coronary artery disease, venous thrombosis, pulmonary embolism, differential interference contras, diabetes mellitus, pulmonary hypertension, surgery/trauma-induced…

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  Fig. 2. Effects of interaction between activated platelets and the immune system. (a) Resting Platelet-specific receptors, including the glycoproteins GPIIb/IIIa, GPIb, GPVI, CD73, MHC class I and FcγR are expressed by resting platelets. Resting platelets express MHC Class I in the lack of costimulatory compounds and express ectonucleosidase CD73, which inhibits CD8+ T cells that convert AMP into the anti-inflammatory properties’ adenosine. Resting platelets also express FcγR, which assists in removing circulating immune complexes. (b) Activated platelets produce DAMPs such as calprotectin and HMGB1, molecules like sP-selectin and sCD40L, as well as serotonin and cytokines like IL-1. Additionally, activated platelets cause the extrusion of mitochondria and mtDNA towards the extracellular environment. APCs grab platelet antigens, which then remove immune complexes for processing and presentation to the immune system. Besides, platelets also express MHC class I and co-stimulatory molecules CD86/CD80. They directly present antigens to CD8+ T cells, promoting their activation. Platelet activation reset surface glycoproteins, such as P-selectin and CD40L, aiding in intercellular communication…

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  Fig. 3. Clinical anti-platelet strategies to target the immune system. These strategies include targeting platelet activation, platelet-immune cell interaction, and platelet-endothelial cell interaction. (a) Targeting platelet activation. Platelet activation can be inhibited by various methods such as inhibiting agonist engagement. This includes targeting ADP binding to its receptor P2Y12 with medications like ticlopidine, clopidogrel, prasugrel, ticagrelor and cangrelor. Other medications include inhibiting platelet 12-LOX activity using VLX-1005, inhibiting platelet COX activity using aspirin, inhibiting FcγR activation using high-dose IVIg, inhibiting TLR7 activation using hydroxychloroquine, inhibiting the NNLRP3 inflammasome with colchicine and MCC950, inhibiting IP receptor with medications like epoprostenol, selexipag and ralinepag and inhibiting intracellular signaling pathways including inhibiting AMPK activation with metformin, inhibiting SYK activation with fostamatinib and sovleplenib and inhibiting (BTK activation with medications like pirtobrutinib, nemtabrutinib, zanubrutinib, and rilzabrutinib. (b) Targeting platelet-immune cell interaction. The interactions of…