Small but mighty: Platelets as central effectors of host defense

Summary

Platelets actively participate in inflammatory processes and drive diseases such as atherosclerosis, rheumatoid arthritis and cancer metastasis. However, platelets also have anti-inflammatory and anti-infective properties, which have received less consideration in the past. In this review, we highlight recent findings on the role of platelets in host defense and describe regulatory pathways modulating immuneresponses. Furthermore, we discuss the role of platelets for the resolution of inflammation and tissue repair. These conceptual changes contribute to our understanding of platelet biology in disease.

Keywords

Platelet immunology - Inflammation - platelet physiology - sepsis - leukocyte function / activation

• References

• 1 Semple JW. et al. Platelets and the immune continuum. Nat Rev Immunol 2011; 11: 264-274
• 2 Morrell CN. et al. Emerging roles for platelets as immune and inflammatory cells. Blood 2014; 123: 2759-2767
• 3 Ross R.. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340: 115-126
• 4 Boilard E. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327: 580-583
• 5 Khan SY. et al. Soluble CD40 ligand accumulates in stored blood components, primes neutrophils through CD40, and is a potential cofactor in the development of transfusion-related acute lung injury. Blood 2006; 108: 2455-2462
• 6 Smyth SS. et al. Platelet functions beyond haemostasis. J Thromb Haemost 2009; 7: 1759-1766
• 7 Cox D. et al. Platelets and the innate immune system: mechanisms of bacterial-induced platelet activation. J Thromb Haemost 2011; 9: 1097-1107
• 8 Lam FW. et al. Platelets and Their Interactions with Other Immune Cells. Compr Physiol 2015; 5: 1265-1280
• 9 Gros A. et al. Platelets in inflammation: regulation of leukocyte activities and vascular repair. Front Immunol 2014; 5: 678
• 10 Lindemann S. et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J Cell Biol 2001; 154: 485-490
• 11 Zuchtriegel G. et al. Platelets Guide Leukocytes to Their Sites of Extravasation. PLoS Biol 2016; 14: e1002459
• 12 Weyrich AS.. Platelets: more than a sack of glue. Hematology Am Soc Hematol Educ Program 2014; 2014: 400-403
• 13 Hartwig H. et al. Platelet-derived PF4 reduces neutrophil apoptosis following arterial occlusion. Thromb Haemost 2014; 111: 562-564
• 14 Scheuerer B. et al. The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood 2000; 95: 1158-1166
• 15 Peerschke EI. et al. Platelet activation by C1q results in the induction of alpha IIb/beta 3 integrins (GPIIb-IIIa) and the expression of P-selectin and procoagulant activity. J Exp Med 1993; 178: 579-587
• 16 Nguyen T. et al. Staphylococcus aureus protein A recognizes platelet gC1qR/p33: a novel mechanism for staphylococcal interactions with platelets. Infect Immun 2000; 68: 2061-2068
• 17 Riaz AH. et al. Human platelets efficiently kill IgG-opsonized E. coli. FEMS Immunol Med Microbiol 2012; 65: 78-83
• 18 von Hundelshausen P. et al. Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium. Blood 2005; 105: 924-930
• 19 Brandt E. et al. The beta-thromboglobulins and platelet factor 4: blood platelet-derived CXC chemokines with divergent roles in early neutrophil regulation. J Leukoc Biol 2000; 67: 471-478
• 20 Shiraki R. et al. Expression of Toll-like receptors on human platelets. Thromb Res 2004; 113: 379-385
• 21 von Hundelshausen P. et al. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 2001; 103: 1772-1777
• 22 Mei J. et al. CXCL5 regulates chemokine scavenging and pulmonary host defense to bacterial infection. Immunity 2010; 33: 106-117
• 23 Zarbock A. et al. Platelet-neutrophil-interactions: linking haemostasis and inflammation. Blood Rev 2007; 21: 99-111
• 24 Moore KL. et al. Identification of a specific glycoprotein ligand for P-selectin (CD62) on myeloid cells. J Cell Biol 1992; 118: 445-456
• 25 Engelmann B, Massberg S.. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13: 34-45
• 26 Schulz C. et al. Platelet GPVI binds to collagenous structures in the core region of human atheromatous plaque and is critical for atheroprogression in vivo. Basic Res Cardiol 2008; 103: 356-367
• 27 Assoian RK. et al. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization J Biol Chem 1983; 258: 7155-7160
• 28 Lievens D. et al. Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood 2010; 116: 4317-4327
• 29 Stark K. et al. Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood 2016. Epub ahead of print
• 30 Bennett JS.. Structure and function of the platelet integrin alphaIIbbeta3. J Clin Invest 2005; 115: 3363-3369
• 31 Jin DK. et al. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nature Med 2006; 12: 557-567
• 32 Diacovo TG. et al. A functional integrin ligand on the surface of platelets: intercellular adhesion molecule-2. J Clin Invest 1994; 94: 1243-1251
• 33 Kraemer BF. et al. Novel anti-bacterial activities of beta-defensin 1 in human platelets: suppression of pathogen growth and signaling of neutrophil extracellular trap formation. PLoS Pathog 2011; 7: e1002355
• 34 Youssefian T. et al. Host defense role of platelets: engulfment of HIV and Staphylococcus aureus occurs in a specific subcellular compartment and is enhanced by platelet activation. Blood 2002; 99: 4021-4029
• 35 Krijgsveld J. et al. Thrombocidins, microbicidal proteins from human blood platelets, are C-terminal deletion products of CXC chemokines. J Biol Chem 2000; 275: 20374-20381
• 36 Yeaman MR. et al. Platelet microbicidal proteins and neutrophil defensin disrupt the Staphylococcus aureus cytoplasmic membrane by distinct mechanisms of action. J Clin Invest 1998; 101: 178-187
• 37 Yeaman MR. et al. Purification and in vitro activities of rabbit platelet microbicidal proteins. Infect Immun 1997; 65: 1023-1031
• 38 Cole AM. et al. Cutting edge: IFN-inducible ELR-CXC chemokines display defensin-like antimicrobial activity. J Immunol 2001; 167: 623-627
• 39 Kerrigan SW. et al. A role for glycoprotein Ib in Streptococcus sanguis-induced platelet aggregation. Blood 2002; 100: 509-516
• 40 McMorran BJ. et al. Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum. Science 2012; 338: 1348-1351
• 41 Aslam R. et al. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood 2006; 107: 637-641
• 42 Semple JW. et al. Platelet-bound lipopolysaccharide enhances Fc receptor-mediated phagocytosis of IgG-opsonized platelets. Blood 2007; 109: 4803-4805
• 43 Schulz C. et al. Crossroads of coagulation and innate immunity: the case of deep vein thrombosis. J Thromb Haemost 2013; 11 Suppl [phone]
• 44 Palabrica T. et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359: 848-851
• 45 Clark SR. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nature Med 2007; 13: 463-469
• 46 Massberg S. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nature Med 2010; 16: 887-896
• 47 Etulain J. et al. P-selectin promotes neutrophil extracellular trap formation in mice. Blood 2015; 126: 242-246
• 48 Maugeri N. et al. Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J Thromb Haemost 2014; 12: 2074-2088
• 49 Brinkmann V. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532-1535
• 50 Jaillon S. et al. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J Exp Med 2007; 204: 793-804
• 51 Fuchs TA. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 2010; 107: 15880-15885
• 52 Reinhardt C. et al. Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation. J Clin Invest 2008; 118: 1110-1122
• 53 Jasuja R. et al. Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents. J Clin Invest 2012; 122: 2104-2113
• 54 Cho J. et al. A critical role for extracellular protein disulfide isomerase during thrombus formation in mice. J Clin Invest 2008; 118: 1123-1131
• 55 Schulz C. et al. Identification of novel downstream targets of platelet glycoprotein VI activation by differential proteome analysis: implications for thrombus formation. Blood 2010; 115: 4102-4110
• 56 Muller F. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139: 1143-1156
• 57 Smith SA. et al. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci USA 2006; 103: 903-908
• 58 Johnson LL. et al. Fibrin-mediated protection against infection-stimulated immunopathology. J Exp Med 2003; 197: 801-806
• 59 Frick IM. et al. The contact system--a novel branch of innate immunity generating antibacterial peptides. EMBO J 2006; 25: 5569-5578
• 60 Yeaman MR.. Platelets in defense against bacterial pathogens. Cell Mol Life Sci 2010; 67: 525-544
• 61 Fitzgerald JR. et al. The interaction of bacterial pathogens with platelets. Nat Rev Microbiol 2006; 4: 445-457
• 62 Mangold A. et al. Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ Res 2015; 116: 1182-1192
• 63 Riegger J. et al. Histopathological evaluation of thrombus in patients presenting with stent thrombosis. A multicenter European study: a report of the prevention of late stent thrombosis by an interdisciplinary global European effort consortium. Eur Heart J 2016; 37: 1538-1549
• 64 von Bruhl ML. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209: 819-835
• 65 Martinod K. et al. Neutrophil elastase-deficient mice form neutrophil extracellular traps in an experimental model of deep vein thrombosis. J Thromb Haemost 2016; 14: 551-558
• 66 Savchenko AS. et al. VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. Blood 2014; 123: 141-148
• 67 Wuescher LM. et al. A novel conditional platelet depletion mouse model reveals the importance of platelets in protection against Staphylococcus aureus bacteremia. J Thromb Haemost 2015; 13: 303-313
• 68 McMorran BJ. et al. Platelets kill intraerythrocytic malarial parasites and mediate survival to infection. Science 2009; 323: 797-800
• 69 Sullam PM. et al. Effect of thrombocytopenia on the early course of streptococcal endocarditis. J Infect Dis 1993; 168: 910-914
• 70 Dankert J. et al. Platelet microbicidal activity is an important defense factor against viridans streptococcal endocarditis. J Infect Dis 2001; 184: 597-605
• 71 Dankert J. et al. Involvement of bactericidal factors from thrombin-stimulated platelets in clearance of adherent viridans streptococci in experimental infective endocarditis. Infect Immun 1995; 63: 663-671
• 72 Wong CH. et al. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat Immunol 2013; 14: 785-792
• 73 Verschoor A. et al. A platelet-mediated system for shuttling blood-borne bacteria to CD8alpha+ dendritic cells depends on glycoprotein GPIb and complement C3. Nat Immunol 2011; 12: 1194-1201
• 74 Broadley SP. et al. Dual-Track Clearance of Circulating Bacteria Balances Rapid Restoration of Blood Sterility with Induction of Adaptive Immunity. Cell Host Microbe 2016; 20: 36-48
• 75 Tisoncik JR. et al. Into the eye of the cytokine storm. Microbiol Mol Biol Rev 2012; 76: 16-32
• 76 Schulte W. et al. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets--an updated view. Mediators Inflamm 2013; 2013: 165974
• 77 Remick DG. et al. Six at six: interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days. Shock 2002; 17: 463-467
• 78 Turnbull IR. et al. Antibiotics improve survival in sepsis independent of injury severity but do not change mortality in mice with markedly elevated interleukin 6 levels. Shock 2004; 21: 121-125
• 79 McInnes IB, Schett G.. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 2007; 7: 429-442
• 80 Feghali CA, Wright TM.. Cytokines in acute and chronic inflammation. Front Biosci 1997; 2: d12-26
• 81 Moudgil KD, Choubey D.. Cytokines in autoimmunity: role in induction, regulation, and treatment. J Interferon Cytokine Res 2011; 31: 695-703
• 82 O’Shea JJ. et al. Cytokines and autoimmunity. Nat Rev Immunol 2002; 2: 37-45
• 83 Moreau D. et al. Platelet count decline: an early prognostic marker in critically ill patients with prolonged ICU stays. Chest 2007; 131: 1735-1741
• 84 Sharma B. et al. Thrombocytopenia in septic shock patients--a prospective observational study of incidence, risk factors and correlation with clinical outcome. Anaesth Intensive Care 2007; 35: 874-880
• 85 Levi M, Ten Cate H.. Disseminated intravascular coagulation. N Engl J Med 1999; 341: 586-592
• 86 Rittirsch D. et al. Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008; 8: 776-787
• 87 Goerge T. et al. Inflammation induces hemorrhage in thrombocytopenia. Blood 2008; 111: 4958-4964
• 88 Loria GD. et al. Platelets support a protective immune response to LCMV by preventing splenic necrosis. Blood 2013; 121: 940-950
• 89 Xiang B. et al. Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signalling pathway. Nat Commun 2013; 4: 2657
• 90 Corken A. et al. Platelet glycoprotein Ib-IX as a regulator of systemic inflammation. Arterioscler Thromb Vasc Biol 2014; 34: 996-1001
• 91 Badimon L. et al. Role of Platelet-Derived Microvesicles As Crosstalk Mediators in Atherothrombosis and Future Pharmacology Targets: A Link between Inflammation, Atherosclerosis, and Thrombosis. Front Pharmacol 2016; 7: 293
• 92 Gudbrandsdottir S. et al. Activated platelets enhance IL-10 secretion and reduce TNF-alpha secretion by monocytes. J Immunol 2013; 191: 4059-4067
• 93 Sadallah S. et al. Microparticles (ectosomes) shed by stored human platelets downregulate macrophages and modify the development of dendritic cells. J Immunol 2011; 186: 6543-6552
• 94 Ando Y. et al. Platelets attenuate production of cytokines and nitric oxide by macrophages in response to bacterial endotoxin. Platelets 2016; 27: 344-350
• 95 Looney MR. et al. Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury. J Clin Invest 2009; 119: 3450-3461
• 96 Yin H. et al. Role for platelet glycoprotein Ib-IX and effects of its inhibition in endotoxemia-induced thrombosis, thrombocytopenia, and mortality. Arterioscler Thromb Vasc Biol 2013; 33: 2529-2537
• 97 Schauer C. et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nature Med 2014; 20: 511-517
• 98 Sadallah S. et al. Ectosomes released by platelets induce differentiation of CD4+T cells into T regulatory cells. Thromb Haemost 2014; 112: 1219-1229
• 99 Shi G. et al. Platelet factor 4 limits Th17 differentiation and cardiac allograft rejection. J Clin Invest 2014; 124: 543-552
• 100 Chakraverty R.. An unexpected role for platelets in blocking Th17 differentiation. J Clin Invest 2014; 124: 480-482
• 101 Dinkla S. et al. Platelet microparticles inhibit IL-17 production by regulatory T cells through P-selectin. Blood 2016; 127: 1976-1986
• 102 Buckner JH.. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol 2010; 10: 849-859
• 103 Fontenot JD. et al. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4: 330-336
• 104 Dominguez-Villar M. et al. Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nature Med 2011; 17: 673-675
• 105 Ueno A. et al. Increased prevalence of circulating novel IL-17 secreting Foxp3 expressing CD4+ T cells and defective suppressive function of circulating Foxp3+ regulatory cells support plasticity between Th17 and regulatory T cells in inflammatory bowel disease patients. Inflamm Bowel Dis 2013; 19: 2522-2534
• 106 Bovenschen HJ. et al. Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest Dermatol 2011; 131: 1853-1860
• 107 Crist SA. et al. Nuclear factor of activated T cells (NFAT) mediates CD154 expression in megakaryocytes. Blood 2008; 111: 3553-3561
• 108 Beaulieu LM. et al. Interleukin 1 receptor 1 and interleukin 1beta regulate megakaryocyte maturation, platelet activation, and transcript profile during inflammation in mice and humans. Arterioscler Thromb Vasc Biol 2014; 34: 552-564
• 109 D’Atri LP. et al. Expression and functionality of Toll-like receptor 3 in the megakaryocytic lineage. J Thromb Haemost 2015; 13: 839-850
• 110 Beaulieu LM. et al. Regulatory effects of TLR2 on megakaryocytic cell function. Blood 2011; 117: 5963-5974
• 111 Rondina MT, Weyrich AS.. Regulation of the genetic code in megakaryocytes and platelets. J Thromb Haemost 2015; 13 Suppl (01) S26-32
• 112 Laffont B. et al. Activated platelets can deliver mRNA regulatory Ago2*microRNA complexes to endothelial cells via microparticles. Blood 2013; 122: 253-261
• 113 Risitano A. et al. Platelets and platelet-like particles mediate intercellular RNA transfer. Blood 2012; 119: 6288-6295
• 114 Serhan CN. et al. Resolution of inflammation: state of the art, definitions and terms. FASEB J 2007; 21: 325-332
• 115 Serhan CN.. Pro-resolving lipid mediators are leads for resolution physiology. Nature 2014; 510: 92-101
• 116 Serhan CN. et al. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 2008; 8: 349-361
• 117 Hoffmann PR. et al. Interaction between phosphatidylserine and the phosphatidylserine receptor inhibits immune responses in vivo. J Immunol 2005; 174: 1393-1404
• 118 Huynh ML. et al. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest 2002; 109: 41-50
• 119 Li MO. et al. Phosphatidylserine receptor is required for clearance of apoptotic cells. Science 2003; 302: 1560-1563
• 120 Serhan CN, Savill J.. Resolution of inflammation: the beginning programs the end. Nat Immunol 2005; 6: 1191-1197
• 121 Buckley CD. et al. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity 2014; 40: 315-327
• 122 Serhan CN. et al. Lipid mediators in the resolution of inflammation. Cold Spring Harb Perspect Biol 2015; 7: a016311
• 123 Norling LV, Serhan CN.. Profiling in resolving inflammatory exudates identifies novel anti-inflammatory and pro-resolving mediators and signals for termination. J Intern Med 2010; 268: 15-24
• 124 Perretti M, D’Acquisto F.. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat Rev Immunol 2009; 9: 62-70
• 125 Dalli J. et al. Proresolving and tissue-protective actions of annexin A1-based cleavage-resistant peptides are mediated by formyl peptide receptor 2/lipoxin A4 receptor. J Immunol 2013; 190: 6478-6487
• 126 Wallace JL. et al. Gaseous mediators in resolution of inflammation. Semin Immunol 2015; 27: 227-233
• 127 Caliendo G. et al. Synthesis and biological effects of hydrogen sulfide (H2S): development of H2S-releasing drugs as pharmaceuticals. J Med Chem 2010; 53: 6275-6286
• 128 Dalli J. et al. The Regulation of Proresolving Lipid Mediator Profiles in Baboon Pneumonia by Inhaled Carbon Monoxide. Am J Respir Cell Mol Biol 2015; 53: 314-325
• 129 Chiang N. et al. Inhaled carbon monoxide accelerates resolution of inflammation via unique proresolving mediator-heme oxygenase-1 circuits. J Immunol 2013; 190: 6378-6388
• 130 Hasko G, Cronstein B.. Regulation of inflammation by adenosine. Front Immunol 2013; 4: 85
• 131 Koroskenyi K. et al. Involvement of adenosine A2A receptors in engulfment-dependent apoptotic cell suppression of inflammation. J Immunol 2011; 186: 7144-7155
• 132 Csoka B. et al. Adenosine promotes alternative macrophage activation via A2A and A2B receptors. FASEB J 2012; 26: 376-386
• 133 Mirakaj V. et al. Vagus nerve controls resolution and pro-resolving mediators of inflammation. The Journal of experimental medicine 2014; 211: 1037-1048
• 134 Pavlov VA, Tracey KJ.. The vagus nerve and the inflammatory reflex--linking immunity and metabolism. Nat Rev Endocrinol 2012; 8: 743-754
• 135 Basil MC, Levy BD.. Specialized pro-resolving mediators: endogenous regulators of infection and inflammation. Nat Rev Immunol 2016; 16: 51-67
• 136 Romano M, Serhan CN.. Lipoxin generation by permeabilized human platelets. Biochemistry 1992; 31: 8269-8277
• 137 Fiore S, Serhan CN.. Formation of lipoxins and leukotrienes during receptor-mediated interactions of human platelets and recombinant human granulocyte/macrophage colony-stimulating factor-primed neutrophils. J Exp Med 1990; 172: 1451-1457
• 138 Serhan CN, Sheppard KA.. Lipoxin formation during human neutrophil-platelet interactions. Evidence for the transformation of leukotriene A4 by platelet 12-lipoxygenase in vitro. J Clin Invest 1990; 85: 772-780
• 139 Tang K. et al. Microparticles mediate enzyme transfer from platelets to mast cells: a new pathway for lipoxin A4 biosynthesis. Biochem Biophys Res Commun 2010; 400: 432-436
• 140 Godson C. et al. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J Immunol 2000; 164: 1663-1667
• 141 Abdulnour RE. et al. Maresin 1 biosynthesis during platelet-neutrophil interactions is organ-protective. Proc Natl Acad Sci USA 2014; 111: 16526-16531
• 142 Gong J. et al. Maresin 1 mitigates LPS-induced acute lung injury in mice. Br J Pharmacol 2014; 171: 3539-3550
• 143 Hong S. et al. Maresin-like lipid mediators are produced by leukocytes and platelets and rescue reparative function of diabetes-impaired macrophages. Chem Biol 2014; 21: 1318-1329
• 144 Eldering JA. et al. Presence of lipocortins I and IV, but not II and VI, in human platelets. FEBS Lett 1993; 318: 231-234
• 145 Murphy CT. et al. Evidence for the presence and location of annexins in human platelets. Biochem Biophys Res Commun 1992; 189: 1739-1746
• 146 Walther A. et al. A novel ligand of the formyl peptide receptor: annexin I regulates neutrophil extravasation by interacting with the FPR. Mol Cell 2000; 5: 831-840
• 147 Zouki C. et al. The anti-inflammatory peptides, antiflammins, regulate the expression of adhesion molecules on human leukocytes and prevent neutrophil adhesion to endothelial cells. FASEB J 2000; 14: 572-580
• 148 Fredman G, Serhan CN.. Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution. Biochem J 2011; 437: 185-197
• 149 Akbiyik F. et al. Human bone marrow megakaryocytes and platelets express PPARgamma, and PPARgamma agonists blunt platelet release of CD40 ligand and thromboxanes. Blood 2004; 104: 1361-1368
• 150 Croasdell A. et al. PPARgamma and the Innate Immune System Mediate the Resolution of Inflammation. PPAR Res 2015; 2015: 549691
• 151 Sidhu JS. et al. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces circulating platelet activity in patients without diabetes mellitus who have coronary artery disease. Am Heart J 2004; 147: e25
• 152 Rao F. et al. PPARgamma ligands decrease hydrostatic pressure-induced platelet aggregation and proinflammatory activity. PloS one 2014; 9: e89654
• 153 Chu CS. et al. Effects of rosiglitazone alone and in combination with atorvastatin on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Am J Cardiol 2006; 97: 646-650
• 154 Ray DM. et al. Peroxisome proliferator-activated receptor gamma and retinoid X receptor transcription factors are released from activated human platelets and shed in microparticles. Thromb Haemost 2008; 99: 86-95
• 155 Gurtner GC. et al. Wound repair and regeneration. Nature 2008; 453: 314-321
• 156 Langer HF. et al. Platelet derived bFGF mediates vascular integrative mechanisms of mesenchymal stem cells in vitro. J Mol Cell Cardiol 2009; 47: 315-325
• 157 Crowley ST. et al. Platelet-induced vascular smooth muscle cell proliferation is modulated by the growth amplification factors serotonin and adenosine diphosphate. Circulation 1994; 90: 1908-1918
• 158 Walsh TG. et al. The functional role of platelets in the regulation of angiogenesis. Platelets 2015; 26: 199-211
• 159 Chandraratne S. et al. Critical role of platelet glycoprotein ibalpha in arterial remodeling. Arterioscler Thromb Vasc Biol 2015; 35: 589-597
• 160 Stellos K. et al. Platelet-derived stromal cell-derived factor-1 regulates adhesion and promotes differentiation of human CD34+ cells to endothelial progenitor cells. Circulation 2008; 117: 206-215
• 161 Massberg S. et al. Platelets secrete stromal cell-derived factor 1alpha and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo. J Exp Med 2006; 203: 1221-1233
• 162 Bermudez DM. et al. Inhibition of stromal cell-derived factor-1alpha further impairs diabetic wound healing. J Vasc Surg 2011; 53: 774-784
• 163 Barrientos S. et al. Growth factors and cytokines in wound healing. Wound Repair Regen 2008; 16: 585-601
• 164 Li L. et al. PDGF-induced proliferation in human arterial and venous smooth muscle cells: molecular basis for differential effects of PDGF isoforms. J Cell Biochem 2011; 112: 289-298
• 165 Lindahl P. et al. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997; 277: 242-245
• 166 Battinelli EM. et al. Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis. Blood 2011; 118: 1359-1369
• 167 Mehta VB, Besner GE.. HB-EGF promotes angiogenesis in endothelial cells via PI3-kinase and MAPK signaling pathways. Growth Factors 2007; 25: 253-263
• 168 Nurden AT.. Platelets, inflammation and tissue regeneration. Thromb Haemost 2011; 105 Suppl (01) S13-33
• 169 Margolis DJ. et al. Clinical protocol: Phase I trial to evaluate the safety of H5.020CMV PDGF-B for the treatment of a diabetic insensate foot ulcer. Wound Repair Regen 2000; 8: 480-493
• 170 Golebiewska EM, Poole AW.. Platelet secretion: From haemostasis to wound healing and beyond. Blood Rev 2015; 29: 153-162
• 171 Embil JM. et al. Recombinant human platelet-derived growth factor-BB (becaplermin) for healing chronic lower extremity diabetic ulcers: an open-label clinical evaluation of efficacy. Wound Repair Regen 2000; 8: 162-168
• 172 Ollivier V. et al. Collagen can selectively trigger a platelet secretory phenotype via glycoprotein VI. PloS one 2014; 9: e104712
• 173 Milioli M. et al. Quantitative proteomics analysis of platelet-derived microparticles reveals distinct protein signatures when stimulated by different physiological agonists. J Proteomics 2015; 121: 56-66
• 174 Velez P. et al. A 2D-DIGE-based proteomic analysis reveals differences in the platelet releasate composition when comparing thrombin and collagen stimulations. Sci Rep 2015; 5: 8198
• 175 Klockenbusch C. et al. Global proteome analysis identifies active immunoproteasome subunits in human platelets. Mol Cell Proteomics 2014; 13: 3308-3319
• 176 Zufferey A. et al. Characterization of the platelet granule proteome: evidence of the presence of MHC1 in alpha-granules. J Proteomics 2014; 101: 130-140
• 177 Sehgal S, Storrie B.. Evidence that differential packaging of the major platelet granule proteins von Willebrand factor and fibrinogen can support their differential release. J Thromb Haemost 2007; 5: 2009-2016
• 178 Chatterjee M. et al. Distinct platelet packaging, release, and surface expression of proangiogenic and antiangiogenic factors on different platelet stimuli. Blood 2011; 117: 3907-3911
• 179 Italiano Jr. JE. et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 2008; 111: 1227-1233
• 180 Pokrovskaya ID. et al. STEM tomography reveals that the canalicular system and alpha-granules remain separate compartments during early secretion stages in blood platelets. J Thromb Haemost 2016; 14: 572-584
• 181 Ghasemzadeh M. et al. The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi. Blood 2013; 121: 4555-4566
• 182 Kulkarni S. et al. Conversion of platelets from a proaggregatory to a proinflammatory adhesive phenotype: role of PAF in spatially regulating neutrophil adhesion and spreading. Blood 2007; 110: 1879-1886