Platelet Biology: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Escribese M. M..

Platelets are generated from megakaryocytes in a multi-step process called thrombopoiesis regulated by thrombopoietin. Thrombopoietin stimulates its receptor in megakaryocytes to induce the genesis of pro-platelets via a mechanism activated by low platelet counts. Platelet counts in blood are controlled by the rates of production and removal, involving mechanisms of platelet clearance, activation or ageing. Platelets are the most numerous circulating cell type (≈200,000/µL blood in humans) with an immune function. 

  • platelets
  • mediators
  • inflammation
  • allergy

1. Platelets as Coagulation Factors

The traditionally attributed role of platelets is to assure hemostasis. Platelets become rapidly activated and adhere tightly to other platelets and to the wall vessel as soon as damage is found. Briefly, platelets bind to von Willebrand factor (vWF), which forms a bridge with exposed collagen on the injury and glycoprotein Ib (GPIb)/V/IX receptor complex on the platelet membrane. The exposed collagen also binds directly to platelet GPIa/IIa and GPVI receptors to induce platelet activation in a positive feedback loop. Platelets then release mediators such as ADP and serotonin that activate platelet G protein-coupled receptors. This process results in increased levels of cytosolic calcium and activates signaling pathways leading to platelet shape change and activation of integrins, enhancing the adhesion of platelets to the endothelial wall. Furthermore, ADP acts on platelet P2Y1 and P2Y12 G-protein-coupled receptors to sustain platelet activation [7,8][1][2]. Finally, the activation of the GPIIb/IIIa receptor results in the cross-linking of fibrinogen or vWF with their receptors (integrin aIIbβ3) leading to platelet aggregation. This promotes the recruitment of additional platelets to the site of vascular injury allowing the formation of the thrombus [9,10][3][4].
Platelets also participate in biological processes such as vascular integrity, tissue regeneration and angiogenesis, and lymphatic vessel development [11,12,13,14,15,16,17,18][5][6][7][8][9][10][11][12].

2. Platelets as Immune Mediators

Platelets count with several organelles such as mitochondria, lysosomes and peroxisomes, and a plethora of intracellular immune mediators stored in granules and vesicles [19][13]. Moreover, platelets express a high number of membrane receptors and contain cytoplasmic mRNA, which can synthetize a limited number of proteins and miRNA [4,9][14][3]. These receptors and proteins allow them to interact with leukocytes and endothelial cells, both by contact-dependent mechanisms and through secreted immune mediators. Thus, platelets can modulate immune responses at the sites of platelet activation systemically [20][15].
Platelet receptors and the molecules stored in platelet granules govern platelet functions. These molecules are listed in Table 1. There are three types of platelet granules: α-granules, dense granules and lysosomal granules. Additionally, a potential new type of granule termed a T-granule has been described [21][16]. α-granules are the most numerous (50–60 per platelet) and largest (200–400 nm) granules. They contain a large variety of proteins, close to 300, including a diverse range of chemokines, such as CXCL1, platelet factor 4 (PF4), CXCL5, CXCL7, CXCL12, macrophage inflammatory protein (MIP)-1α and regulated on activation normal T expressed and secreted (RANTES) [22][17]. Dense granules are smaller (~150 nm), less abundant (3–8 per platelet) and store small molecules, such as ADP, ATP, inorganic polyphosphate, pyrophosphate, histamine, serotonin, and calcium. Finally, lysosomal granules are sparse and contain proteases and glycosidases [10,23][4][18]. Upon platelet stimulation, granules undergo regulated exocytosis and release their content into the extracellular environment. In addition, molecules found on the inner granule membrane become surface-expressed. Many of these granule-derived molecules are immune mediators.
Table 1.
 Summary of major platelet-derived inflammatory mediators and membrane receptors.
α-Granules
No. Molecule Function
1 PF4 (CXCL4) Chemokine: Induce leukocyte pro-inflammatory cytokine release in monocyte, neutrophil, and T-cell recruitment; Th differentiation
2 P-selectin Adhesion molecule: Formation of platelet-leukocyte aggregate; Formation of bridges between leukocytes and endothelium
3 CD40L TNF superfamily: antigen-presenting cell activation, B-cell responses, endothelial cell activation
4 MIP-1a (CCL3) Cytokine: neutrophil and eosinophil activation, B-cell immunoglobulin production
5 IL-1β Cytokine: acute phase response, leukocyte and endothelial activation
6 RANTES (CCL5) Chemokine: Promotes monocyte, macrophage and T cell recruitment
7 TGF-β Cytokine: cell proliferation, T-cell differentiation, B-cell and macrophage phenotype regulation
8 PDGF Growth factor: cell growth and differentiation, monocyte/macrophage differentiation
9 VWF Platelet adhesion, PMN extravasation
10 CD63 Tetraspanin: transmembrane adaptor protein, leukocyte recruitment
11 SDF-1 Chemokine: T-cell, monocyte, and PMN chemotaxis
12 VEGF Growth factor: angiogenesis, adhesion molecule expression
13 Ppbp β-thromboglobulin (NAP-2) Chemokine: neutrophil activation and recruitment, macrophage phagocytic activity
14 Thrombospondins Apoptosis, endothelial cell inflammation, macrophage-platelet aggregates
15 MMP-2, MMP-9 Protease: extracellular matrix breakdown, platelet-leukocyte aggregate formation
16 Cyclophilin A Vascular smooth muscle cell growth factor
18 CXCL1, CXCL5, CXCL7, CXCL12 Chemokines
19 Microbial proteins Cationic proteins: disrupt cell membrane
Dense Granule
No. Molecule Immune/Inflammatory Role
1 Serotonin DC and T-cell functions
2 Glutamate T-cell trafficking
3 Polyphosphates Inflammatory response amplification
4 ADP Platelet, leukocyte, endothelial cell activation
5 Histamine Increased vessel reactivity and degranulation
6 ATP, phosphate, calcium Fuel cell and co-factors in thrombosis
7 Eicosanoids Pro-inflammatory signals
Produced Metabolites
No. Molecule Immune/Inflammatory Role
1 Thromboxane Eicosanoid: T-cell differentiation, monocyte activation
2 Nitric oxide Reactive oxygen species: anti-inflammatory and antithrombotic
3 GPIbα Adhesion molecule: binds Mac-1 on leukocytes
4 TXA2 Mediator that enhance platelet activation
5 S1P Active metabolite which activate platelets and stimulate mitogenesis
6 PAF Bioactive lipid: induce endothelial migration
7 Chrondroitin sulfate Metabolite released by platelets after trigger complement activation
8 LPA Lipid: ligand of G protein-coupled receptors
Membrane Receptors
No. Molecule Immune/Inflammatory Role
1 TLR1, TLR2, TLR4, TLR6, TRL8 and TLR9 Receptors that recognize pathogen-associated molecular patterns and mediate inflammatory events
2 CD40, CD40L Receptor: Mediator of interactions between lymphocytes and antigen presenting cells
3 GPIa, GPIIb/IIIa, GPIc-IIa (VLA-6) Platelet glycoprotein: adhesion molecules
4 GPVI Collagen receptor: induces powerful platelet activation
5 P2X1 Receptor is involved in platelet shape change and in activation by collagen
6 P2Y1, P2Y12 G-protein receptors: sustain platelet activation in response to ADP
7 PAR-1, PAR-4 Thrombin activates platelets through proteolytic cleavage of PAR receptors
8 ICAM-2, Adhesion molecule
10 JAM-A, Protects from thrombosis by suppressing integrin αIIbβ3
NOTE: ADP, adenosine 5′-diphosphate; CD40L, CD40 ligand; DC, dendritic cell; GPIba, glycoprotein Iba; 5-HT, 5-hydroxytryptamin; IL, interleukin; LPA, lysophosphatydic acid; MIP, macrophage-inflammatory protein; MMP, metalloproteinase; NAP, neutrophil-activating peptide; PAFR, platelet-activating factor receptor; PAR, protease-activated receptors; PDGF, platelet-derived growth factor; PF4, platelet factor 4; PMN, neutrophil; ppbp, proplatelet basic protein; SDF, stromal cell–derived factor; SP1, sphingosine-1-phosphate; TGF, transforming growth factor; Th, T helper; TLR, toll-like receptor; TNF, tumor necrosis factor; TxA2, Thromboxane A2; VEGF, vascular endothelial growth factor; VWF, von Willebrand factor.
This is the case of P-selectin, which is one of the most bioactive molecules contained in α-granules and involved in inflammation. It promotes platelet aggregation and platelet-endothelial and platelet-leukocyte interactions [24][19]. Other α-granule constituents such as PF4 or RANTES are immune mediators that recruit and activate immune cells or induce endothelial cell inflammation [25,26][20][21]. The inflammatory roles of most α-granule-derived chemokines, cytokines and adhesion molecules are well described. However, the direct contribution of dense granule constituents to immune responses is still largely unexplored. It is nevertheless known that serotonin, contained in dense granules, increases monocyte differentiation into dendritic cells (DCs) [27][22] and early naïve T-cell activation [28][23]. Moreover, platelets can recruit and activate DCs via integrin alphaMbeta2 (Mac-1) [29][24]. In addition, DC expression of T-cell co-stimulatory molecules CD80 and CD86 is increased by activated platelets in a contact-independent manner leading to a stronger and more rapid T-cell response [30][25]. In turn, T cells may activate platelets through a T-cell CD40L/platelet CD40 interaction leading to platelet release of RANTES and further T-cell recruitment [31][26]. Platelets are also the major source of soluble CD40L, which induces B-cell production of immunoglobulin (Ig)G, by activating DCs and promoting B-cell isotype switching [24][19]. It has also been suggested that platelets enhance signals needed for adaptive humoral immunity and germinal center formation [32][27].
Activated platelets also release interleukin-1β (IL-1β), which is not granule-stored but produced upon platelet stimulation [33][28]. Typical markers of platelet activation (granule exocytosis and integrin expression) are increased rapidly after platelet stimulation (seconds to minutes), but the release of IL-1β from stimulated platelets occurs over hours [34][29].
Platelets affect all phases of immune responses. Their interactions with immune cells likely mediate beneficial outcomes in limiting infection and maintaining hemostasis [35][30]. However, continued platelet interactions with leukocytes or endothelial cells can also lead to adverse effects from excessive immune stimulation and inflammatory insult [4][14].

3. Metabolic Plasticity of Platelets

Despite being small and lacking a nucleus, platelets possess extraordinary metabolic machinery. The metabolism of platelets is not fully known yet; however, it has been estimated that at their basal metabolic state, ATP is generated by both mitochondrial oxidative phosphorylation (OXPHOS) (35%) and glycolysis (65%) [36][31]. During platelet activation, fatty acid oxidation and glutaminolysis is promoted to meet the energetic needs for aggregation [36][31]. Fatty acids and L-glutamine are required for OXPHOS, and if necessary, platelets can uptake extracellular fatty acids [36][31]. Interestingly, platelets proved to have metabolic plasticity, which allows them to compensate the energetic demand driven by activation and aggregation switching from one to another metabolic route [36][31]. These two important ATP-generating pathways have become relevant in translational research, where it has been observed that severe phenotypes of allergic and respiratory diseases show a bioenergetic dysfunction in platelets and leukocytes [37][32]. As an example of dysfunction, decreased glycolytic function in platelets from asthmatic patients has shown to be compensated by increased tricarboxylic acid (TCA) cycle activity leading to a re-direction of their metabolism towards mitochondrial metabolism, which might increase oxidative injury in asthma [38][33].

References

  1. Coller, B.S.; Shattil, S.J. The GPIIb/IIIa (integrin αIIbβ3) odyssey: A technology-driven saga of a receptor with twists, turns, and even a bend. Blood 2008, 112, 3011–3025.
  2. Plow, E.F.; Meller, J.; Byzova, T.V. Integrin function in vascular biology: A view from 2013. Curr. Opin. Hematol. 2014, 21, 241–247.
  3. Deppermann, C.; Kubes, P. Platelets and infection. Semin. Immunol. 2016, 28, 536–545.
  4. Thomas, M.R.; Storey, R.F. The role of platelets in inflammation. Thromb. Haemost. 2015, 114, 449–458.
  5. Ho-Tin-Noe, B.; Demers, M.; Wagner, D.D. How platelets safeguard vascular integrity. J. Thromb. Haemost. 2011, 9, S56–S65.
  6. Koenen, R.R. The prowess of platelets in immunity and inflammation. Thromb. Haemost. 2016, 116, 605–612.
  7. Hess, P.R.; Rawnsley, D.R.; Jakus, Z.; Yang, Y.; Sweet, D.T.; Fu, J.; Herzog, B.; Lu, M.; Nieswandt, B.; Oliver, G.; et al. Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life. J. Clin. Investig. 2014, 124, 273–284.
  8. Franco, A.T.; Corken, A.; Ware, J. Platelets at the interface of thrombosis, inflammation, and cancer. Blood 2015, 126, 582–588.
  9. Evans, C.M.; Fingerlin, T.E.; Schwarz, M.I.; Lynch, D.; Kurche, J.; Warg, L.; Yang, I.V.; Schwartz, D.A. Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways. Physiol. Rev. 2016, 96, 1567–1591.
  10. Welsh, J.D.; Kahn, M.L.; Sweet, D.T. Lymphovenous hemostasis and the role of platelets in regulating lymphatic flow and lymphatic vessel maturation. Blood 2016, 128, 1169–1173.
  11. Rondina, M.T.; Weyrich, A.S.; Zimmerman, G.A. Platelets as cellular effectors of inflammation in vascular diseases. Circ. Res. 2013, 112, 1506–1519.
  12. Maeda, T.; Wakasawa, T.; Shima, Y.; Tsuboi, I.; Aizawa, S.; Tamai, I. Role of polyamines derived from arginine in differentiation and proliferation of human blood cells. Biol. Pharm. Bull. 2006, 29, 234–239.
  13. Zapata, J.C.; Cox, D.; Salvato, M.S. The role of platelets in the pathogenesis of viral hemorrhagic fevers. PLoS Negl. Trop. Dis. 2014, 8, e2858.
  14. Morrell, C.N.; Aggrey, A.A.; Chapman, L.M.; Modjeski, K.L. Emerging roles for platelets as immune and inflammatory cells. Blood 2014, 123, 2759–2767.
  15. Smyth, S.S.; McEver, R.P.; Weyrich, A.S.; Morrell, C.N.; Hoffman, M.R.; Arepally, G.M.; French, P.A.; Dauerman, H.L.; Becker, R.C.; Platelet Colloquium, P. Platelet functions beyond hemostasis. J. Thromb. Haemost. 2009, 7, 1759–1766.
  16. Thon, J.N.; Peters, C.G.; Machlus, K.R.; Aslam, R.; Rowley, J.; Macleod, H.; Devine, M.T.; Fuchs, T.A.; Weyrich, A.S.; Semple, J.W.; et al. T granules in human platelets function in TLR9 organization and signaling. J. Cell Biol. 2012, 198, 561–574.
  17. Maynard, D.M.; Heijnen, H.F.; Horne, M.K.; White, J.G.; Gahl, W.A. Proteomic analysis of platelet α-granules using mass spectrometry. J. Thromb. Haemost. 2007, 5, 1945–1955.
  18. Koseoglu, S.; Flaumenhaft, R. Advances in platelet granule biology. Curr. Opin. Hematol. 2013, 20, 464–471.
  19. Nurden, A.T. Platelets, inflammation and tissue regeneration. Thromb. Haemost. 2011, 105, S13–S33.
  20. Blair, P.; Flaumenhaft, R. Platelet alpha-granules: Basic biology and clinical correlates. Blood Rev. 2009, 23, 177–189.
  21. Deppermann, C.; Cherpokova, D.; Nurden, P.; Schulz, J.N.; Thielmann, I.; Kraft, P.; Vogtle, T.; Kleinschnitz, C.; Dutting, S.; Krohne, G.; et al. Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice. J. Clin. Investig. 2013.
  22. Katoh, N.; Soga, F.; Nara, T.; Tamagawa-Mineoka, R.; Nin, M.; Kotani, H.; Masuda, K.; Kishimoto, S. Effect of serotonin on the differentiation of human monocytes into dendritic cells. Clin. Exp. Immunol. 2006, 146, 354–361.
  23. Leon-Ponte, M.; Ahern, G.P.; O’Connell, P.J. Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor. Blood 2007, 109, 3139–3146.
  24. Langer, H.F.; Daub, K.; Braun, G.; Schonberger, T.; May, A.E.; Schaller, M.; Stein, G.M.; Stellos, K.; Bueltmann, A.; Siegel-Axel, D.; et al. Platelets recruit human dendritic cells via Mac-1/JAM-C interaction and modulate dendritic cell function in vitro. Arterioscler Thromb Vasc. Biol. 2007, 27, 1463–1470.
  25. Hagihara, M.; Higuchi, A.; Tamura, N.; Ueda, Y.; Hirabayashi, K.; Ikeda, Y.; Kato, S.; Sakamoto, S.; Hotta, T.; Handa, S.; et al. Platelets, after exposure to a high shear stress, induce IL-10-producing, mature dendritic cells in vitro. J. Immunol. 2004, 172, 5297–5303.
  26. Danese, S.; de la Motte, C.; Reyes, B.M.; Sans, M.; Levine, A.D.; Fiocchi, C. Cutting edge: T cells trigger CD40-dependent platelet activation and granular RANTES release: A novel pathway for immune response amplification. J. Immunol. 2004, 172, 2011–2015.
  27. Elzey, B.D.; Tian, J.; Jensen, R.J.; Swanson, A.K.; Lees, J.R.; Lentz, S.R.; Stein, C.S.; Nieswandt, B.; Wang, Y.; Davidson, B.L.; et al. Platelet-mediated modulation of adaptive immunity. A communication link between innate and adaptive immune compartments. Immunity 2003, 19, 9–19.
  28. Lindemann, S.; Tolley, N.D.; Dixon, D.A.; McIntyre, T.M.; Prescott, S.M.; Zimmerman, G.A.; Weyrich, A.S. Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J. Cell Biol. 2001, 154, 485–490.
  29. Brown, G.T.; McIntyre, T.M. Lipopolysaccharide signaling without a nucleus: Kinase cascades stimulate platelet shedding of proinflammatory IL-1β-rich microparticles. J. Immunol. 2011, 186, 5489–5496.
  30. Shi, G.; Field, D.J.; Ko, K.A.; Ture, S.; Srivastava, K.; Levy, S.; Kowalska, M.A.; Poncz, M.; Fowell, D.J.; Morrell, C.N. Platelet factor 4 limits Th17 differentiation and cardiac allograft rejection. J. Clin. Investig. 2014, 124, 543–552.
  31. Ravi, S.; Chacko, B.; Sawada, H.; Kramer, P.A.; Johnson, M.S.; Benavides, G.A.; O′Donnell, V.; Marques, M.B.; Darley-Usmar, V.M. Metabolic plasticity in resting and thrombin activated platelets. PLoS ONE 2015, 10, e0123597.
  32. Obeso, D.; Mera-Berriatua, L.; Rodriguez-Coira, J.; Rosace, D.; Fernandez, P.; Martin-Antoniano, I.A.; Santaolalla, M.; Marco Martin, G.; Chivato, T.; Fernandez-Rivas, M.; et al. Multi-omics analysis points to altered platelet functions in severe food-associated respiratory allergy. Allergy 2018, 73, 2137–2149.
  33. Xu, W.; Cardenes, N.; Corey, C.; Erzurum, S.C.; Shiva, S. Platelets from Asthmatic Individuals Show Less Reliance on Glycolysis. PLoS ONE 2015, 10, e0132007.
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