Neutrophil extracellular traps (NETs) and the role of platelets in infection

Summary

In addition to playing a central role in normal haemostasis, platelets make important contributions to host inflammatory and immune responses to injury or infection. Under pathophysiological conditions where platelet function is not tightly controlled, platelets also play critical roles in pathogenic processes underlying cardiovascular disease, uncontrolled inflammation, coagulopathy and in tumour metastasis. Neutrophil extracellular traps (NETs) are webs of histone-modified nuclear material extruded from activated neutrophils during inflammatory responses and these degranulation events can be directly triggered by platelet/neutrophil engagement. Emerging research describes how NETs influence platelet function, particularly in the setting of infection and inflammation. Especially intriguing is the potential for platelet-driven coagulation to be modulated by NETs in plasma and interstitial spaces. These findings also reveal new perspectives related to improved therapy for venous thrombosis.

Keywords

Platelets - infection - inflammation - neutrophil extracellular traps (NETs)

• References

• 1 Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood 2014; 123: 2768-2776.
• 2 Jenne CN. et al. Platelets: bridging hemostasis, inflammation, and immunity. Int J Lab Hematol 2013; 35: 254-261.
• 3 Rondina MT. et al. Platelets as cellular effectors of inflammation in vascular diseases. Circ Res 2013; 112: 1506-1519.
• 4 Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol 2007; 5: 577-582.
• 5 O’Donoghue AJ. et al. Global substrate profiling of proteases in human neutrophil extracellular traps reveals consensus motif predominantly contributed by elastase. PLoS ONE 2013; 8: e75141.
• 6 Brinkmann V. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532-1535.
• 7 Brill A. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 2012; 10: 136-144.
• 8 McDonald B. et al. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 2012; 12: 324-333.
• 9 Rossaint J. et al. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood 2014; 123: 2573-2584.
• 10 Meng W. et al. Depletion of neutrophil extracellular traps in vivo results in hypersusceptibility to polymicrobial sepsis in mice. Crit Care 2012; 16: R137.
• 11 Ombrello C. et al. Our expanding view of platelet functions and its clinical implications. J Cardiovas Translat Res 2010; 3: 538-546.
• 12 Kuter DJ. Milestones in understanding platelet production: a historical overview. Brit J Haematol 2014; 165: 248-258.
• 13 Gardiner EE, Andrews RK. Platelet receptor expression and shedding: Glyco-protein Ib-IX-V and glycoprotein VI. Transf Med Rev 2014; 28: 56-60.
• 14 Jackson SP. et al. Dynamics of platelet thrombus formation. J Thromb Haemost 2009; 7: 17-20.
• 15 Berndt MC. et al. Primary haemostasis: newer insights. Haemophilia 2014; 20: 15-22.
• 16 McFadyen JD, Jackson SP. Differentiating haemostasis from thrombosis for therapeutic benefit. Thromb Haemostas 2013; 110: 859-867.
• 17 Boulaftali Y. et al. Platelet immunoreceptor tyrosine-based activation motif (ITAM) signalling and vascular integrity. Circ Res 2014; 114: 1174-1184.
• 18 Flad HD, Brandt E. Platelet-derived chemokines: pathophysiology and therapeutic aspects. Cell Mol Life Sci 2010; 67: 2363-2386.
• 19 Blair P, Flaumenhaft R. Platelet alpha-granules: basic biology and clinical correlates. Blood Rev 2009; 23: 177-189.
• 20 Gardiner EE. et al. GPIbαα-selective activation of platelets induces platelet signalling events comparable to GPVI activation events. Platelets 2010; 21: 244-252.
• 21 Bergmeier W, Stefanini L. Platelet ITAM signalling. Curr Opin Hematol 2013; 20: 445-450.
• 22 Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor?. Blood 2003; 102: 449-461.
• 23 Arthur JF. et al. Glycoprotein VI is associated with GPIb-IX-V on the membrane of resting and activated platelets. Thromb Haemost 2005; 93: 716-723.
• 24 Andrews RK. et al. The glycoprotein Ib-IX-V complex. In: Platelets. 2nd ed.. Academic Press; San Diego, CA: 2006. pp. 145-163.
• 25 Romo GM. et al. The glycoprotein Ib-IX-V complex is a platelet counterreceptor for P-selectin. J Exp Med 1999; 190: 803-814.
• 26 Simon DI. et al. Platelet glycoprotein Ibαα is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med 2000; 192: 193-204.
• 27 Inoue O. et al. Laminin stimulates spreading of platelets through integrinα 1-dependent activation of GPVI. Blood 2006; 107: 1405-1412.
• 28 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.
• 29 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13: 34-45.
• 30 Semple JW. et al. Platelets and the immune continuum. Nat Rev Immunol 2011; 11: 264-274.
• 31 Cox D. et al. Platelets and the innate immune system: mechanisms of bacterial-induced platelet activation. J Thromb Haemost 2011; 9: 1097-1107.
• 32 Morrell CN. et al. Emerging roles for platelets as immune and inflammatory cells. Blood 2014; 123: 2759-2767.
• 33 Fitzgerald JR. et al. The interaction of bacterial pathogens with platelets. Nat Rev Microbiol 2006; 4: 445-457.
• 34 Hu H. et al. GPVI and GPIb mediate Staphylococcal Superantigen-Like Protein 5 (SSL5) induced platelet activation and direct toward glycans as potential inhibitors. PLoS ONE 2011; 6: e19190.
• 35 Armstrong PC. et al. Staphylococcal superantigen-like protein 5 induces thrombotic and bleeding complications in vivo: inhibition by an anti-SSL5 antibody and the glycan Bimosiamose. J Thromb Haemost 2012; 10: 2607-2609.
• 36 De Haas CJC. et al. Staphylococcal superantigen-like 5 activates platelets and supports platelet adhesion under flow conditions, which involves glycoprotein Ibα and αIIbβ3. J Thromb Haemost 2009; 7: 1867-1874.
• 37 Arman M. et al. Amplification of bacteria-induced platelet activation is triggered by FcγγRIIA, integrin ααIIbββ3 and platelet factor 4. Blood 2014; 123: 3166-3174.
• 38 Tilley DO. et al. Glycoprotein Iband Fc RIIa play key roles in platelet activation by the colonizing bacterium, Streptococcus oralis . J Thromb Haemost 2013; 11: 941-950.
• 39 Boilard E. et al. Influenza virus H1N1 activates platelets through Fc RIIA signalling and thrombin generation. Blood 2014; 123: 2854-2863.
• 40 Cuker A. Recent advances in heparin-induced thrombocytopenia. Curr Opin Hematol 2011; 18: 315-322.
• 41 Krauel K. et al. Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes. Blood 2012; 120: 3345-3352.
• 42 Krauel K. et al. Platelet factor 4 binds to bacteria, inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia. Blood 2011; 117: 1370-1378.
• 43 Aslam R. et al. Platelet toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-production in vivo. Blood 2006; 107: 637-641.
• 44 Beaulieu LM, Freedman JE. The role of inflammation in regulating platelet production and function: Toll-like receptors in platelets and megakaryocytes. Thromb Res 2010; 125: 205-209.
• 45 Koupenova M. et al. Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis. Blood. 2014 in press.
• 46 Garraud O. et al. Pathogen sensing, subsequent signalling, and signalosome in human platelets. Thromb Res 2011; 127: 283-286.
• 47 Berthet J. et al. Human platelets can discriminate between various bacterial LPS isoforms via TLR4 signalling and differential cytokine secretion. Clin Immunol 2012; 145: 189-200.
• 48 Rex S. et al. Immune versus thrombotic stimulation of platelets differentially regulates signalling pathways, intracellular protein-protein interactions, and alpha-granule release. Thromb Haemost 2009; 102: 97-110.
• 49 Bruserud Ø. Bidirectional crosstalk between platelets and monocytes initiated by Toll-like receptor: An important step in the early defense against fungal infections?. Platelets 2013; 24: 85-97.
• 50 Falker K. et al. The toll-like receptor 2/1 (TLR2/1) complex initiates human platelet activation via the src/Syk/LAT/PLCγγ2 signalling cascade. Cell Signal 2014; 26: 279-286.
• 51 Smyth SS. et al. 3-Integrin-deficient mice but not P-selectin-deficient mice develop intimal hyperplasia after vascular injury : correlation with leukocyte recruitment to adherent platelets 1 hour after injury. Circulation 2001; 103: 2501-2507.
• 52 Cerletti C. et al. Platelet-leukocyte interactions in thrombosis. Thromb Res 2012; 129: 263-266.
• 53 Fuentes QE. et al. Role of platelets as mediators that link inflammation and thrombosis in atherosclerosis. Platelets 2013; 24: 255-262.
• 54 Totani L, Evangelista V. Platelet-leukocyte interactions in cardiovascular disease and beyond. Arterioscl Thromb Vasc Biol 2010; 30: 2357-2361.
• 55 Piccardoni P. et al. Platelet/polymorphonuclear leukocyte adhesion: a new role for SRC kinases in Mac-1 adhesive function triggered by P-selectin. Blood 2001; 98: 108-116.
• 56 Ehlers R. et al. Targeting platelet-leukocyte interactions: Identification of the integrin Mac-1 binding site for the platelet counter receptor Glycoprotein Ibαα. J Exp Med 2003; 198: 1077-1088.
• 57 Boilard E. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327: 580-583.
• 58 Mayne E. et al. Increased platelet and microparticle activation in HIV infection: upregulation of P-selectin and tissue factor expression. J Acquir Immune Defic Syndr 2012; 59: 340-346.
• 59 Garcia BA. et al. The platelet microparticle proteome. J Proteome Res 2005; 4: 1516-1521.
• 60 Duerschmied D. et al. Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood 2013; 121: 1008-1015.
• 61 Brown GT, McIntyre TM. Lipopolysaccharide signalling without a nucleus: kinase cascades stimulate platelet shedding of proinflammatory IL-1ββ-rich microparticles. J Immunol 2011; 186: 5489-5496.
• 62 Prasad KSS. et al. Soluble CD40 ligand induces ββ3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signalling. Proc Natl Acad Sci USA 2003; 100: 12367-12371.
• 63 Andre P. et al. Platelet-derived CD40L: the switch-hitting player of cardiovascular disease. Circ 2002; 106: 896-899.
• 64 van Holten TC. et al. Quantitative proteomics analysis reveals similar release profiles following specific PAR-1 or PAR-4 stimulation of platelets. Cardiovasc Res 2014; 103: 140-146.
• 65 Stone PC, Nash GB. Conditions under which immobilized platelets activate as well as capture flowing neutrophils. Br J Haematol 1999; 105: 514-522.
• 66 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.
• 67 Ghasemzadeh M. et al. The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi. Blood 2013; 121: 4555-4566.
• 68 Weyrich AS. et al. Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest 1996; 97: 1525-1534.
• 69 Li P. et al. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 2010; 207: 1853-1862.
• 70 Leshner M. et al. PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extra-cellular trap-like structures. Front Immunol 2012; 3: 307.
• 71 Kessenbrock K. et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 2009; 15: 623-625.
• 72 Papayannopoulos V. et al. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 2010; 191: 677-691.
• 73 Itakura A, McCarty OJT. Pivotal role for the mTOR pathway in the formation of neutrophil extracellular traps via regulation of autophagy. Am J Physiol Cell Physiol 2013; 305: C348-C354.
• 74 McInturff AM. et al. Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 alpha. Blood 2012; 120: 3118-3125.
• 75 Hermosilla C. et al. The intriguing host innate immune response: novel anti-parasitic defence by neutrophil extracellular traps. Parasitology 2014; 1-10.
• 76 Fuchs TA. et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 2007; 176: 231-241.
• 77 Bianchi M. et al. Restoration of anti-Aspergillus defense by neutrophil extracellular traps in human chronic granulomatous disease after gene therapy is calprotectin-dependent. J Allergy Clin Immunol 2011; 127: 1243-1252e1247.
• 78 Urban CF. et al. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol 2006; 8: 668-676.
• 79 Beiter K. et al. An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Current Biol 2006; 16: 401-407.
• 80 Yipp BG, Kubes P. NETosis: how vital is it?. Blood 2013; 122: 2784-2794.
• 81 Luo HR, Loison F. Constitutive neutrophil apoptosis: Mechanisms and regulation. Am J Hematol 2008; 83: 288-295.
• 82 Pilsczek FH. et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol 2010; 185: 7413-7425.
• 83 Yipp BG. et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med 2012; 18: 1386-1393.
• 84 Clark SR. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13: 463-469.
• 85 Nauseef WM. Nyet to NETs? A pause for healthy skepticism. J Leuk Biol 2012; 91: 353-355.
• 86 Engelmann B, Spannagl M. Activators, therapeutics and immunity-related aspects of thrombosis. Thromb Haemost 2014; 111: 568-569.
• 87 Fuchs TA. et al. Extracellular DNA traps promote thrombosis. Proc Nat Acad Sci USA 2010; 107: 15880-15885.
• 88 Fuchs TA. et al. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol 2012; 32: 1777-1783.
• 89 Semeraro F. et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 2011; 118: 1952-1961.
• 90 Ward CM. et al. Binding of the von Willebrand factor A1 domain to histone. Thromb Res 1997; 86: 469-477.
• 91 Schauer C. et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med 2014; 20: 511-517.
• 92 Yost CC. et al. Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood 2009; 113: 6419-6427.
• 93 Kambas K. et al. Autophagy mediates the delivery of thrombogenic tissue factor to neutrophil extracellular traps in human sepsis. PloS one 2012; 7: e45427.
• 94 Kambas K. et al. Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease. Ann Rheum Dis. 2013 Epub ahead of print.
• 95 Kwaan HC. Microvascular thrombosis: a serious and deadly pathologic process in multiple diseases. Semin Thromb Hemost 2011; 37: 961-978.
• 96 Demers M, Wagner DD. NETosis: A new factor in tumor progression and cancer-associated thrombosis. Semin Thromb Hemost 2014; 40: 277-283.
• 97 Kambas K. et al. The emerging role of neutrophils in thrombosis-the journey of TF through NETs. Frontiers Immunol 2012; 3: 385.
• 98 Geddings JE, Mackman N. New players in haemostasis and thrombosis. Thromb Haemost 2014; 111: 570-574.
• 99 Hakkim A. et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Nat Acad Sci USA 2010; 107: 9813-9818.
• 100 Garcia-Romo GS. et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med 2011; 3: 73ra20.
• 101 Kling D. et al. Pharmacological control of platelet-leukocyte interactions by the human anti-P-selectin antibody inclacumab--preclinical and clinical studies. Thromb Res 2013; 131: 401-410.
• 102 Tamburrelli C. et al. Epoprostenol inhibits human platelet-leukocyte mixed conjugate and platelet microparticle formation in whole blood. Thromb Res 2011; 128: 446-451.
• 103 Knight JS. et al. Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis. Circ Res 2014; 114: 947-956.
• 104 Savchenko AS. et al. Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development. J Thromb Haemost 2014; 12: 860-870.