Platelet signaling in immune landscape: comprehensive mechanism and clinical therapy

Abstract

Platelets are essential for blood clotting and maintaining normal hemostasis. In pathological conditions, platelets are increasingly recognized as crucial regulatory factors in various immune-mediated inflammatory diseases. Resting platelets are induced by various factors such as immune complexes through Fc receptors, platelet-targeting autoantibodies and other platelet-activating stimuli. Platelet activation in immunological processes involves the release of immune activation stimuli, antigen presentation and interaction with immune cells. Platelets participate in both the innate immune system (neutrophils, monocytes/macrophages, dendritic cells (DCs) and Natural Killer (NK) cells and the adaptive immune system (T and B cells). Clinical therapeutic strategies include targeting platelet activation, platelet-immune cell interaction and platelet-endothelial cell interaction, which display positive development prospects. Understanding the mechanisms of platelets in immunity is important, and developing targeted modulations of these mechanisms will pave the way for promising therapeutic strategies.

Keywords: Clinical strategies; Immunity; Inflammation; Platelet.

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 thrombotic disorders. Platelets are intricately linked to infections and malignancies, including COVID-19, dengue, influenza, hepatitis B/C, sepsis, bacteremia, solid tumors, metastasis and hematological malignancies. Platelets also affect neuroinflammatory diseases, autoimmune diseases, kidney diseases and liver injuries

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 with immune cells. Activated platelets also promote the release of platelet-derived extracellular vesicles that included granules, lysosomes, CD40L, HMGB1, P-selectin and IL-1. Under endothelial cell activation, activated platelet surface receptors like GPIIb/IIIa and PSGL-1 binds to vWF and P-selectin on the endothelium, facilitating communication with immune cells. (c) Innate immunity is stimulated by platelets through interactions between CD40L and CD40, leading to the assembly of platelets with pDCs and boosting the production of IFNα in reaction to bloodstream immune complexes. Platelets communicate with monocytes and neutrophils via various surface receptors, promoting the maturation of monocytes into APCs and stimulating neutrophil activity. Platelets generate mitochondria and mtDNA, which activate neutrophils and cause the creation of NETs. Autoantigens are liberated, dealt with by APCs, and then delivered to lymphocytes. (d) Adaptive immunity is triggered by platelets, which express membrane CD40L and sCD40L, eliciting B cell reactions and the generation of autoantibodies. T_reg cells interact with P-selectin-positive platelets and extracellular vesicles-derived platelets, resulting in the downregulation of transcription factor FOXP3 and affecting T_reg cell function

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 platelet-immune cell are suppressed by affecting specific ligand-receptor pairs that mediate these interactions. For example, antibodies inhibit P-selectin binding to PSGL1 on neutrophils and other immune cells, while antibodies targeting CD40 or CD40L can inhibit interactions with B cells. (c) Targeting platelet-endothelial cell interaction. Activated NOS and COX-1 increase the synthesis of NO and PGI₂ as well as intracellular contents of cAMP and cGMP. Medications like aspirin and NSAIDs act as COX-1 inhibitors to prevent COX-1-induced increased production of PGI₂ and intracellular levels of cAMP. PDE5 inhibitors such as sildenafil, vardenafil, tadalafil and vardenafil limit the hydrolysis of cGMP to inactive 5’GMP. PDE3 inhibitors like cilostazol limit catalyzing the hydrolysis of cAMP to inactive 5’AMP. Prothrombin hydrolyzed activation into thrombin by the TF. Thrombin, activated by TF, can be blocked by medications like heparin and dabigatran. PAR1/4 inhibitors like vorapaxar, BMS-986120 and BMS-986141, which are principal thrombin receptors in platelets. GPIb-V-IX inhibitors like anfibatide inhibit the binding domain of vWF. GPVI inhibitors include revacept, glenzocimab, and eltrombopag. GPIIbIIIa inhibitors such as tirofiban, eptifibatide, abciximab, and XV459 decrease platelet activity by competing with fibrinogen and vWF