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  • Review Article
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Platelets: emerging facilitators of cellular crosstalk in rheumatoid arthritis

Nature Reviews Rheumatology volume 15, pages 237–248 (2019)Cite this article

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Abstract

Rheumatoid arthritis (RA) is an autoimmune disease in which a variety of circulating pro-inflammatory cells and dysregulated molecules are involved in disease aetiology and progression. Platelets are an important cellular element in the circulation that can bind several dysregulated molecules (such as collagen, thrombin and fibrinogen) that are present both in the synovium and the circulation of patients with RA. Platelets not only respond to dysregulated molecules in their environment but also transport and express their own inflammatory mediators, and serve as regulators at the boundary between haemostasis and immunity. Activated platelets also produce microparticles, which further convey signalling molecules and receptors to the synovium and circulation, thereby positioning these platelet-derived particles as strategic regulators of inflammation. These diverse functions come together to make platelets facilitators of cellular crosstalk in RA. Thus, the receptor functions, ligand binding potential and dysregulated signalling pathways in platelets are becoming increasingly important for treatment in RA. This Review aims to highlight the role of platelets in RA and the need to closely examine platelets as health indicators when designing effective pharmaceutical targets in this disease.

Key points

  • Platelets have important immune effector functions in rheumatoid arthritis (RA).

  • Platelet signalling pathways are dysregulated in the presence of pro-inflammatory molecules such as collagen, thrombin, fibrinogen and cytokines.

  • Increased (pro-inflammatory) platelet signalling causes platelets to develop antigen-presenting functions and results in dysregulated intercellular aggregation and pathological clot formation.

  • Activated platelets and their thrombo-inflammatory function in RA represent an important risk factor for thrombosis and cardiovascular comorbidities.

  • Activated platelets produce pro-inflammatory microparticles that are present both in the circulation and in the synovium; these microparticles function in systemic inflammatory processes in RA.

  • In an individualized medicine approach, platelet structure and biochemical markers of inflammation would be used during diagnosis and platelet activity monitored during treatment to track immune responses in RA.

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Fig. 1: Platelet involvement in the pathophysiology of rheumatoid arthritis.
Fig. 2: Platelet–immune cell crosstalk in rheumatoid arthritis.
Fig. 3: Platelet receptors involved in inflammatory signalling in rheumatoid arthritis.
Fig. 4: Platelet αIIbβ3 integrin signalling in rheumatoid arthritis.
Fig. 5: Platelet α2β1 integrin signalling in rheumatoid arthritis.
Fig. 6: Platelet GPVI and FcRγ signalling in rheumatoid arthritis.

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References

  1. Ma, V. Y., Chan, L. & Carruthers, K. J. Incidence, prevalence, costs, and impact on disability of common conditions requiring rehabilitation in the United States: stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Arch. Phys. Med. Rehabil. 95, 986–995 (2014).

    PubMed  PubMed Central  Google Scholar 

  2. Cross, M. et al. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann. Rheum. Dis. 73, 1316–1322 (2014).

    PubMed  Google Scholar 

  3. Rudan, I. et al. Prevalence of rheumatoid arthritis in low- and middle-income countries: a systematic review and analysis. J. Glob. Health 5, 010409 (2015).

    PubMed  PubMed Central  Google Scholar 

  4. Usenbo, A., Kramer, V., Young, T. & Musekiwa, A. Prevalence of arthritis in Africa: a systematic review and meta-analysis. PLoS ONE 10, e0133858 (2015).

    PubMed  PubMed Central  Google Scholar 

  5. Panagopoulos, P. K. & Lambrou, G. I. Bone erosions in rheumatoid arthritis: recent developments in pathogenesis and therapeutic implications. J. Musculoskelet. Neuronal Interact. 18, 304–319 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. Pietraforte, D. et al. Redox control of platelet functions in physiology and pathophysiology. Antioxid. Redox Signal. 21, 177–193 (2014).

    CAS  PubMed  Google Scholar 

  7. Balogh, E. et al. Oxidative stress impairs energy metabolism in primary cells and synovial tissue of patients with rheumatoid arthritis. Arthritis Res. Ther. 20, 95 (2018).

    PubMed  PubMed Central  Google Scholar 

  8. Pretorius, E., Akeredolu, O. O., Soma, P. & Kell, D. B. Major involvement of bacterial components in rheumatoid arthritis and its accompanying oxidative stress, systemic inflammation and hypercoagulability. Exp. Biol. Med. 242, 355–373 (2017).

    CAS  Google Scholar 

  9. Ferrante, E. et al. Determinants of thromboxane biosynthesis in rheumatoid arthritis: Role of RAGE and oxidant stress. Free Radic. Biol. Med. 49, 857–864 (2010).

    CAS  PubMed  Google Scholar 

  10. Staron, A., Makosa, G. & Koter-Michalak, M. Oxidative stress in erythrocytes from patients with rheumatoid arthritis. Rheumatol. Int. 32, 331–334 (2012).

    CAS  PubMed  Google Scholar 

  11. Olumuyiwa-Akeredolu, O. O. & Pretorius, E. Platelet and red blood cell interactions and their role in rheumatoid arthritis. Rheumatol. Int. 35, 1955–1964 (2015).

    CAS  PubMed  Google Scholar 

  12. Olumuyiwa-Akeredolu, O. O., Soma, P., Buys, A. V., Debusho, L. K. & Pretorius, E. Characterizing pathology in erythrocytes using morphological and biophysical membrane properties: Relation to impaired hemorheology and cardiovascular function in rheumatoid arthritis. Biochim. Biophys. Acta Biomembr. 1859, 2381–2391 (2017).

    CAS  PubMed  Google Scholar 

  13. van Breukelen-van der Stoep, D. F., Klop, B., van Zeben, D., Hazes, J. M. & Castro Cabezas, M. Cardiovascular risk in rheumatoid arthritis: how to lower the risk? Atherosclerosis 231, 163–172 (2013).

    Google Scholar 

  14. Mantel, A. et al. Risk factors for the rapid increase in risk of acute coronary events in patients with new-onset rheumatoid arthritis: a nested case-control study. Arthritis Rheumatol. 67, 2845–2854 (2015).

    CAS  PubMed  Google Scholar 

  15. Meyer, P. W. et al. Circulating cytokine profiles and their relationships with autoantibodies, acute phase reactants, and disease activity in patients with rheumatoid arthritis. Mediators Inflamm. 2010, 158514 (2010).

    PubMed  Google Scholar 

  16. Wruck, C. J. et al. Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. Ann. Rheum. Dis. 70, 844–850 (2011).

    CAS  PubMed  Google Scholar 

  17. Veselinovic, M. et al. Oxidative stress in rheumatoid arthritis patients: relationship to diseases activity. Mol. Cell Biochem. 391, 225–232 (2014).

    CAS  PubMed  Google Scholar 

  18. Vasanthi, P., Nalini, G. & Rajasekhar, G. Status of oxidative stress in rheumatoid arthritis. Int. J. Rheum. Dis. 12, 29–33 (2009).

    PubMed  Google Scholar 

  19. Bunescu, A., Seideman, P., Lenkei, R., Levin, K. & Egberg, N. Enhanced Fcgamma receptor I, alphaMbeta2 integrin receptor expression by monocytes and neutrophils in rheumatoid arthritis: interaction with platelets. J. Rheumatol. 31, 2347–2355 (2004).

    CAS  PubMed  Google Scholar 

  20. Tamura, N. et al. Soluble CD154 in rheumatoid arthritis: elevated plasma levels in cases with vasculitis. J. Rheumatol. 28, 2583–2590 (2001).

    CAS  PubMed  Google Scholar 

  21. Is¸ık, M., Sahin, H. & Huseyin, E. New platelet indices as inflammatory parameters for patients with rheumatoid arthritis. Eur. J. Rheumatol. 1, 144–146 (2014).

    Google Scholar 

  22. Yazici, S. et al. The platelet indices in patients with rheumatoid arthritis: mean platelet volume reflects disease activity. Platelets 21, 122–125 (2010).

    CAS  PubMed  Google Scholar 

  23. Milovanovic, M., Nilsson, E. & Jaremo, P. Relationships between platelets and inflammatory markers in rheumatoid arthritis. Clin. Chim. Acta 343, 237–240 (2004).

    CAS  PubMed  Google Scholar 

  24. Gasparyan, A. Y., Stavropoulos-Kalinoglou, A., Mikhailidis, D. P., Douglas, K. M. & Kitas, G. D. Platelet function in rheumatoid arthritis: arthritic and cardiovascular implications. Rheumatol. Int. 31, 153–164 (2011).

    CAS  PubMed  Google Scholar 

  25. Boilard, E. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 327, 580–583 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Lindemann, S. et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1β synthesis. J. Cell Biol. 154, 485–490 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Rosengren, S., Corr, M. & Boyle, D. L. Platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes. Arthritis Res. Ther. 12, R65 (2010).

    PubMed  PubMed Central  Google Scholar 

  28. Ahamed, J. et al. In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1. Blood 112, 3650–3660 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Lefevre, S. et al. Disease-specific effects of matrix and growth factors on adhesion and migration of rheumatoid synovial fibroblasts. J. Immunol. 198, 4588–4595 (2017).

    CAS  PubMed  Google Scholar 

  30. Brown, A. J., Sepuru, K. M., Sawant, K. V. & Rajarathnam, K. Platelet-derived chemokine CXCL7 dimer preferentially exists in the glycosaminoglycan-bound form: implications for neutrophil-platelet crosstalk. Front. Immunol. 8, 1248 (2017).

    PubMed  PubMed Central  Google Scholar 

  31. Fox, J. M. et al. CXCL4/platelet factor 4 is an agonist of CCR1 and drives human monocyte migration. Sci. Rep. 8, 9466 (2018).

    PubMed  PubMed Central  Google Scholar 

  32. Ohyama, K. et al. Immune complexome analysis of serum and its application in screening for immune complex antigens in rheumatoid arthritis. Clin. Chem. 57, 905–909 (2011).

    CAS  PubMed  Google Scholar 

  33. Dyer, K. D. et al. Mouse and human eosinophils degranulate in response to platelet-activating factor (PAF) and lysoPAF via a PAF-receptor-independent mechanism: evidence for a novel receptor. J. Immunol. 184, 6327–6334 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Undas, A. et al. Thrombin generation in rheumatoid arthritis: dependence on plasma factor composition. Thromb. Haemost. 104, 224–230 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang, M. J. et al. Determination of role of thromboxane A2 in rheumatoid arthritis. Discov. Med. 19, 23–32 (2015).

    PubMed  Google Scholar 

  36. Eastgate, J. A., Symons, J. A., Wood, N. C., Capper, S. J. & Duff, G. W. Plasma levels of interleukin-1-alpha in rheumatoid arthritis. Br. J. Rheumatol. 30, 295–297 (1991).

    CAS  PubMed  Google Scholar 

  37. Nishimura, S. et al. IL-1α induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs. J. Cell Biol. 209, 453–466 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Lukasik, Z. M., Makowski, M. & Makowska, J. S. From blood coagulation to innate and adaptive immunity: the role of platelets in the physiology and pathology of autoimmune disorders. Rheumatol. Int. 38, 959–974 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Flad, H. D. & Brandt, E. Platelet-derived chemokines: pathophysiology and therapeutic aspects. Cell. Mol. Life Sci. 67, 2363–2386 (2010).

    CAS  PubMed  Google Scholar 

  40. Habets, K. L., Huizinga, T. W. & Toes, R. E. Platelets and autoimmunity. Eur. J. Clin. Invest. 43, 746–757 (2013).

    CAS  PubMed  Google Scholar 

  41. Henn, V. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391, 591–594 (1998).

    CAS  PubMed  Google Scholar 

  42. Boilard, E., Blanco, P. & Nigrovic, P. A. Platelets: active players in the pathogenesis of arthritis and SLE. Nat. Rev. Rheumatol. 8, 534–542 (2012).

    CAS  PubMed  Google Scholar 

  43. Habets, K. L. et al. Anti-citrullinated protein antibodies contribute to platelet activation in rheumatoid arthritis. Arthritis Res. Ther. 17, 209 (2015).

    PubMed  PubMed Central  Google Scholar 

  44. Hsu, J. et al. Bruton’s tyrosine kinase mediates platelet receptor-induced generation of microparticles: a potential mechanism for amplification of inflammatory responses in rheumatoid arthritis synovial joints. Immunol. Lett. 150, 97–104 (2013).

    CAS  PubMed  Google Scholar 

  45. Schmitt-Sody, M. et al. In vivo interactions of platelets and leucocytes with the endothelium in murine antigen-induced arthritis: the role of P-selectin. Scand. J. Rheumatol. 36, 311–319 (2007).

    CAS  PubMed  Google Scholar 

  46. Manfredi, A. A. et al. Anti-TNFα agents curb platelet activation in patients with rheumatoid arthritis. Ann. Rheum. Dis. 75, 1511–1520 (2016).

    CAS  PubMed  Google Scholar 

  47. Del Rey, M. J. et al. Clinicopathological correlations of podoplanin (gp38) expression in rheumatoid synovium and its potential contribution to fibroblast platelet crosstalk. PLoS ONE 9, e99607 (2014).

    PubMed  PubMed Central  Google Scholar 

  48. Kehrel, B. Platelet-collagen interactions. Semin. Thromb. Hemost. 21, 123–129 (1995).

    CAS  PubMed  Google Scholar 

  49. Haywood, L. & Walsh, D. A. Vasculature of the normal and arthritic synovial joint. Histol. Histopathol. 16, 277–284 (2001).

    CAS  PubMed  Google Scholar 

  50. Kular, J. K., Basu, S. & Sharma, R. I. The extracellular matrix: structure, composition, age-related differences, tools for analysis and applications for tissue engineering. J. Tissue Eng. 5, 2041731414557112 (2014).

    PubMed  Google Scholar 

  51. Hakala, M., Risteli, L., Manelius, J., Nieminen, P. & Risteli, J. Increased type I collagen degradation correlates with disease severity in rheumatoid arthritis. Ann. Rheum. Dis. 52, 866–869 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kwasny-Krochin, B., Gluszko, P. & Undas, A. Unfavorably altered fibrin clot properties in patients with active rheumatoid arthritis. Thromb. Res. 126, 11–16 (2010).

    Google Scholar 

  53. Scinocca, M. et al. Antihomocitrullinated fibrinogen antibodies are specific to rheumatoid arthritis and frequently bind citrullinated proteins/peptides. J. Rheumatol. 41, 270–279 (2014).

    CAS  PubMed  Google Scholar 

  54. Vadseth, C. et al. Pro-thrombotic state induced by post-translational modification of fibrinogen by reactive nitrogen species. J. Biol. Chem. 279, 8820–8826 (2004).

    CAS  PubMed  Google Scholar 

  55. Türk, S. M. et al. Can we predict thrombotic tendency in rheumatoid arthritis? A thromboelastographic analysis (with ROTEM). Clin. Rheumatol. 37, 2341–2349 (2018).

    PubMed  Google Scholar 

  56. Di Franco, M. et al. Possible implication of red blood cells in the prothrombotic risk in early rheumatoid arthritis. J. Rheumatol. 42, 1352–1354 (2015).

    Google Scholar 

  57. Andia, I. Rheumatoid arthritis: the ins and outs of platelets in RA. Nat. Rev. Rheumatol. 13, 262–264 (2017).

    CAS  PubMed  Google Scholar 

  58. Uslu, A. U. et al. Two new inflammatory markers associated with Disease Activity Score-28 in patients with rheumatoid arthritis: neutrophil-lymphocyte ratio and platelet-lymphocyte ratio. Int. J. Rheum. Dis. 18, 731–735 (2015).

    PubMed  Google Scholar 

  59. Zengin, O. et al. New inflammatory markers in early rheumatoid arthritis. Z. Rheumatol. 77, 144–150 (2018).

    CAS  PubMed  Google Scholar 

  60. Rodriguez-Carrio, J. et al. Red cell distribution width is associated with cardiovascular risk and disease parameters in rheumatoid arthritis. Rheumatology 54, 641–646 (2015).

    CAS  PubMed  Google Scholar 

  61. Beinsberger, J., Heemskerk, J. W. & Cosemans, J. M. Chronic arthritis and cardiovascular disease: altered blood parameters give rise to a prothrombotic propensity. Semin. Arthritis Rheum. 44, 345–352 (2014).

    CAS  PubMed  Google Scholar 

  62. Olumuyiwa-Akeredolu, O. O. & Pretorius, E. Rheumatoid arthritis: notable biomarkers linking to chronic systemic conditions and cancer. Curr. Pharm. Des. 22, 918–924 (2016).

    CAS  PubMed  Google Scholar 

  63. Kim, K. W., Kim, B. M., Moon, H. W., Lee, S. H. & Kim, H. R. Role of C-reactive protein in osteoclastogenesis in rheumatoid arthritis. Arthritis Res. Ther. 17, 41 (2015).

    PubMed  PubMed Central  Google Scholar 

  64. Chang, M. K., Binder, C. J., Torzewski, M. & Witztum, J. L. C-Reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: phosphorylcholine of oxidized phospholipids. PNAS 99, 13043–13048 (2002).

    CAS  PubMed  Google Scholar 

  65. Sato, A., Oe, K., Yamanaka, H., Yokoyama, I. & Ebina, K. C-Reactive protein specifically enhances platelet-activating factor-induced inflammatory activity in vivo. Eur. J. Pharmacol. 745, 46–51 (2014).

    CAS  PubMed  Google Scholar 

  66. Biro, E. et al. Activated complement components and complement activator molecules on the surface of cell-derived microparticles in patients with rheumatoid arthritis and healthy individuals. Ann. Rheum. Dis. 66, 1085–1092 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Martinez, M. C., Tesse, A., Zobairi, F. & Andriantsitohaina, R. Shed membrane microparticles from circulating and vascular cells in regulating vascular function. Am. J. Physiol. Heart Circ. Physiol. 288, H1004–H1009 (2005).

    CAS  PubMed  Google Scholar 

  68. Tesse, A. et al. Origin and biological significance of shed-membrane microparticles. Endocr. Metab. Immune Disord. Drug Targets 6, 287–294 (2006).

    CAS  PubMed  Google Scholar 

  69. Connor, D. E., Exner, T., Ma, D. D. & Joseph, J. E. The majority of circulating platelet-derived microparticles fail to bind annexin V, lack phospholipid-dependent procoagulant activity and demonstrate greater expression of glycoprotein Ib. Thromb. Haemost. 103, 1044–1052 (2010).

    CAS  PubMed  Google Scholar 

  70. Ataullakhanov, F. et al. Platelet microparticle membranes have 50- to 100-fold higher specific procoagulant activity than activated platelets. Thromb. Haemost. 97, 425–434 (2017).

    Google Scholar 

  71. Walker, B. et al. Dynamic adhesion of eryptotic erythrocytes to immobilized platelets via platelet phosphatidylserine receptors. Am. J. Physiol. Cell Physiol. 306, C291–C297 (2014).

    CAS  PubMed  Google Scholar 

  72. Knijff-Dutmer, E. A., Koerts, J., Nieuwland, R., Kalsbeek-Batenburg, E. M. & van de Laar, M. A. Elevated levels of platelet microparticles are associated with disease activity in rheumatoid arthritis. Arthritis Rheum. 46, 1498–1503 (2002).

    CAS  PubMed  Google Scholar 

  73. Vinuela-Berni, V. et al. Proportions of several types of plasma and urine microparticles are increased in patients with rheumatoid arthritis with active disease. Clin. Exp. Immunol. 180, 442–451 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Cloutier, N. et al. The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes. EMBO Mol. Med. 5, 235–249 (2013).

    CAS  PubMed  Google Scholar 

  75. Boilard, E. et al. Platelets participate in synovitis via Cox-1-dependent synthesis of prostacyclin independently of microparticle generation. J. Immunol. 186, 4361–4366 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. van Eijk, I. C. et al. Circulating microparticles remain associated with complement activation despite intensive anti-inflammatory therapy in early rheumatoid arthritis. Ann. Rheum. Dis. 69, 1378–1382 (2010).

    PubMed  Google Scholar 

  77. Jenne, C. N., Urrutia, R. & Kubes, P. Platelets: bridging hemostasis, inflammation, and immunity. Int. J. Lab. Hematol. 35, 254–261 (2013).

    CAS  PubMed  Google Scholar 

  78. Smith, T. L. & Weyrich, A. S. Platelets as central mediators of systemic inflammatory responses. Thromb. Res. 127, 391–394 (2011).

    CAS  PubMed  Google Scholar 

  79. von Hundelshausen, P. & Weber, C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ. Res. 100, 27–40 (2007).

    Google Scholar 

  80. Aslam, R. et al. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood 107, 637–641 (2006).

    CAS  PubMed  Google Scholar 

  81. Andonegui, G. et al. Platelets express functional Toll-like receptor-4. Blood 106, 2417–2423 (2005).

    CAS  PubMed  Google Scholar 

  82. Semple, J. W., Italiano, J. E. Jr & Freedman, J. Platelets and the immune continuum. Nat. Rev. Immunol. 11, 264–274 (2011).

    CAS  PubMed  Google Scholar 

  83. Weyrich, A. S., Lindemann, S. & Zimmerman, G. A. The evolving role of platelets in inflammation. J. Thromb. Haemost. 1, 1897–1905 (2003).

    CAS  PubMed  Google Scholar 

  84. Speth, C. et al. Complement and platelets: mutual interference in the immune network. Mol. Immunol. 67, 108–118 (2015).

    CAS  PubMed  Google Scholar 

  85. Thomas, M. R. & Storey, R. F. The role of platelets in inflammation. Thromb. Haemost. 114, 449–458 (2015).

    PubMed  Google Scholar 

  86. Elzey, B. D., Ratliff, T. L., Sowa, J. M. & Crist, S. A. Platelet CD40L at the interface of adaptive immunity. Thromb. Res. 127, 180–183 (2011).

    CAS  PubMed  Google Scholar 

  87. Iannacone, M. Platelet-mediated modulation of adaptive immunity. Semin. Immunol. 28, 555–560 (2016).

    CAS  PubMed  Google Scholar 

  88. Morrell, C. N., Aggrey, A. A., Chapman, L. M. & Modjeski, K. L. Emerging roles for platelets as immune and inflammatory cells. Blood 123, 2759–2767 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Farr, M., Wainwright, A., Salmon, M., Hollywell, C. A. & Bacon, P. A. Platelets in the synovial fluid of patients with rheumatoid arthritis. Rheumatol. Int. 4, 13–17 (1984).

    CAS  PubMed  Google Scholar 

  90. Duchez, A. C. et al. Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A2-IIA. PNAS 112, E3564–E3573 (2015).

    CAS  PubMed  Google Scholar 

  91. Tamagawa-Mineoka, R. Important roles of platelets as immune cells in the skin. J. Dermatol. Sci. 77, 93–101 (2015).

    CAS  PubMed  Google Scholar 

  92. Meyer, A. et al. Platelet TGF-β1 contributions to plasma TGF-β1, cardiac fibrosis, and systolic dysfunction in a mouse model of pressure overload. Blood 119, 1064–1074 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Fu, S. et al. TGF-β induces Foxp3 + T-regulatory cells from CD4 + CD25 - precursors. Am. J. Transplant 4, 1614–1627 (2004).

    CAS  PubMed  Google Scholar 

  94. Lichtman, M. K., Otero-Vinas, M. & Falanga, V. Transforming growth factor beta (TGF-β) isoforms in wound healing and fibrosis. Wound Repair Regen. 24, 215–222 (2016).

    PubMed  Google Scholar 

  95. Gerdes, N. et al. Platelets regulate CD4+ T cell differentiation via multiple chemokines in humans. Thromb. Haemost. 106, 353–362 (2011).

    CAS  PubMed  Google Scholar 

  96. Zhu, L., Huang, Z., Stalesen, R., Hansson, G. K. & Li, N. Platelets provoke distinct dynamics of immune responses by differentially regulating CD4+ T cell proliferation. J. Thromb. Haemost. 12, 1156–1165 (2014).

    CAS  PubMed  Google Scholar 

  97. Kim, S. J. & Jenne, C. N. Role of platelets in neutrophil extracellular trap (NET) production and tissue injury. Semin. Immunol. 28, 546–554 (2016).

    CAS  PubMed  Google Scholar 

  98. Clark, S. R. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med. 13, 463–469 (2007).

    CAS  PubMed  Google Scholar 

  99. Page, C. & Pitchford, S. Neutrophil and platelet complexes and their relevance to neutrophil recruitment and activation. Int. Immunopharmacol. 17, 1176–1184 (2013).

    CAS  PubMed  Google Scholar 

  100. Rong, M. Y. et al. Platelets induce a proinflammatory phenotype in monocytes via the CD147 pathway in rheumatoid arthritis. Arthritis Res. Ther. 16, 478 (2014).

    PubMed  PubMed Central  Google Scholar 

  101. Schmidt, R. et al. Extracellular matrix metalloproteinase inducer (CD147) is a novel receptor on platelets, activates platelets, and augments nuclear factor kappaB-dependent inflammation in monocytes. Circ. Res. 102, 302–309 (2008).

    CAS  PubMed  Google Scholar 

  102. Zamora, C. et al. Functional consequences of platelet binding to T lymphocytes in inflammation. J. Leukoc. Biol. 94, 521–529 (2013).

    CAS  PubMed  Google Scholar 

  103. Nurden, A. T. Platelets, inflammation and tissue regeneration. Thromb. Haemost. 105 (Suppl. 1), 13–33 (2011).

    Google Scholar 

  104. Larsen, E. et al. PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell 59, 305–312 (1989).

    CAS  PubMed  Google Scholar 

  105. Diacovo, T. G., Puri, K. D., Warnock, R. A., Springer, T. A. & von Andrian, U. H. Platelet-mediated lymphocyte delivery to high endothelial venules. Science 273, 252–255 (1996).

    CAS  PubMed  Google Scholar 

  106. van Gils, J. M., Zwaginga, J. J. & Hordijk, P. L. Molecular and functional interactions among monocytes, platelets, and endothelial cells and their relevance for cardiovascular diseases. J. Leukoc. Biol. 85, 195–204 (2009).

    PubMed  Google Scholar 

  107. McEver, R. P. Adhesive interactions of leukocytes, platelets, and the vessel wall during hemostasis and inflammation. Thromb. Haemost. 86, 746–756 (2001).

    CAS  PubMed  Google Scholar 

  108. Sreeramkumar, V. et al. Neutrophils scan for activated platelets to initiate inflammation. Science 346, 1234–1238 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Dinkla, S. et al. Platelet microparticles inhibit IL-17 production by regulatory T cells through P-selectin. Blood 127, 1976–1986 (2016).

    CAS  PubMed  Google Scholar 

  110. Wang, F., Wang, N. S., Yan, C. G., Li, J. H. & Tang, L. Q. The significance of platelet activation in rheumatoid arthritis. Clin. Rheumatol. 26, 768–771 (2007).

    PubMed  Google Scholar 

  111. Chapman, L. M. et al. Platelets present antigen in the context of MHC class I. J. Immunol. 189, 916–923 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Zufferey, A. et al. Characterization of the platelet granule proteome: evidence of the presence of MHC1 in alpha-granules. J. Proteomics 101, 130–140 (2014).

    CAS  PubMed  Google Scholar 

  113. Zufferey, A. et al. Mature murine megakaryocytes present antigen-MHC class I molecules to T cells and transfer them to platelets. Blood Adv. 1, 1773–1785 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Cunin, P. et al. Megakaryocytes compensate for Kit insufficiency in murine arthritis. J. Clin. Invest. 127, 1714–1724 (2017).

    PubMed  PubMed Central  Google Scholar 

  115. Niu, G. & Chen, X. Why integrin as a primary target for imaging and therapy. Theranostics 1, 30–47 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Jones, J. L. & Walker, R. A. Integrins: a role as cell signalling molecules. Mol. Pathol. 52, 208–213 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Coller, B. S. αIIbβ3: structure and function. J. Thromb. Haemost. 13 (Suppl. 1), 17–25 (2015).

    Google Scholar 

  118. Bennett, J. S. Structure and function of the platelet integrin αIIbβ3. J. Clin. Invest. 115, 3363–3369 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Durrant, T. N., van den Bosch, M. T. & Hers, I. Integrin αIIbβ3 outside-in signaling. Blood 130, 1607–1619 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Li, Z., Delaney, M. K., O’Brien, K. A. & Du, X. Signaling during platelet adhesion and activation. Arterioscler. Thromb. Vasc. Biol. 30, 2341–2349 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Qiao, J. et al. NLRP3 regulates platelet integrin αIIbβ3 outside-in signaling, hemostasis and arterial thrombosis. Haematologica 103, 1568–1576 (2018).

    PubMed  PubMed Central  Google Scholar 

  122. Boylan, B. et al. Identification of FcγRIIa as the ITAM-bearing receptor mediating αIIbβ3 outside-in integrin signaling in human platelets. Blood 112, 2780–2786 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhi, H. et al. Platelet activation and thrombus formation over IgG immune complexes requires integrin αIIbβ3 and Lyn kinase. PLoS ONE 10, e0135738 (2015).

    PubMed  PubMed Central  Google Scholar 

  124. Lu, W. J. et al. Role of a Janus kinase 2-dependent signaling pathway in platelet activation. Thromb. Res. 133, 1088–1096 (2014).

    CAS  PubMed  Google Scholar 

  125. Arman, M. & Krauel, K. Human platelet IgG Fc receptor FcγRIIA in immunity and thrombosis. J. Thromb. Haemost. 13, 893–908 (2015).

    CAS  PubMed  Google Scholar 

  126. Cloutier, N. et al. Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration. PNAS 115, E1550–E1559 (2018).

    CAS  PubMed  Google Scholar 

  127. Lowin, T. & Straub, R. H. Integrins and their ligands in rheumatoid arthritis. Arthritis Res. Ther. 13, 244 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Wollheim, F. A. Predictors of joint damage in rheumatoid arthritis. APMIS 104, 81–93 (1996).

    CAS  PubMed  Google Scholar 

  129. Bledzka, K., Smyth, S. S. & Plow, E. F. Integrin αIIbβ3: from discovery to efficacious therapeutic target. Circ. Res. 112, 1189–1200 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Tung, C. H., Lu, M. C., Lai, N. S. & Wu, S. F. Tumor necrosis factor-alpha blockade treatment decreased CD154 (CD40-ligand) expression in rheumatoid arthritis. PLoS ONE 12, e0183726 (2017).

    PubMed  PubMed Central  Google Scholar 

  131. Guo, Y. et al. CD40L-dependent pathway is active at various stages of rheumatoid arthritis disease progression. J. Immunol. 198, 4490–4501 (2017).

    CAS  PubMed  Google Scholar 

  132. Charafeddine, A. H. et al. Platelet-derived CD154: ultrastructural localization and clinical correlation in organ transplantation. Am. J. Transplant 12, 3143–3151 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Kyburz, D. et al. Human rheumatoid factor production is dependent on CD40 signaling and autoantigen. J. Immunol. 163, 3116–3122 (1999).

    CAS  PubMed  Google Scholar 

  134. May, F. et al. CLEC-2 is an essential platelet-activating receptor in hemostasis and thrombosis. Blood 114, 3464–3472 (2009).

    CAS  PubMed  Google Scholar 

  135. Navarro-Nunez, L., Langan, S. A., Nash, G. B. & Watson, S. P. The physiological and pathophysiological roles of platelet CLEC-2. Thromb. Haemost. 109, 991–998 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Gitz, E. et al. CLEC-2 expression is maintained on activated platelets and on platelet microparticles. Blood 124, 2262–2270 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Mullazehi, M., Mathsson, L., Lampa, J. & Ronnelid, J. High anti-collagen type-II antibody levels and induction of proinflammatory cytokines by anti-collagen antibody-containing immune complexes in vitro characterise a distinct rheumatoid arthritis phenotype associated with acute inflammation at the time of disease onset. Ann. Rheum. Dis. 66, 537–541 (2007).

    CAS  PubMed  Google Scholar 

  138. Peters, M. A. et al. The loss of α2β1 integrin suppresses joint inflammation and cartilage destruction in mouse models of rheumatoid arthritis. Arthritis Rheum. 64, 1359–1368 (2012).

    CAS  PubMed  Google Scholar 

  139. Jung, S. M. et al. Collagen-type specificity of glycoprotein VI as a determinant of platelet adhesion. Platelets 19, 32–42 (2008).

    CAS  PubMed  Google Scholar 

  140. Nieswandt, B. & Watson, S. P. Platelet-collagen interaction: is GPVI the central receptor? Blood 102, 449–461 (2003).

    CAS  PubMed  Google Scholar 

  141. Koivula, M. K. et al. Antibodies binding to citrullinated telopeptides of type I and type II collagens and to mutated citrullinated vimentin synergistically predict the development of seropositive rheumatoid arthritis. Ann. Rheum. Dis. 71, 1666–1670 (2012).

    CAS  PubMed  Google Scholar 

  142. Manivel, V. A. et al. Anti-type II collagen immune complex-induced granulocyte reactivity is associated with joint erosions in RA patients with anti-collagen antibodies. Arthritis Res. Ther. 17, 8 (2015).

    PubMed  PubMed Central  Google Scholar 

  143. Cook, A. D., Rowley, M. J., Mackay, I. R., Gough, A. & Emery, P. Antibodies to type II collagen in early rheumatoid arthritis. Correlation with disease progression. Arthritis Rheum. 39, 1720–1727 (1996).

    CAS  PubMed  Google Scholar 

  144. Schulz, C. et al. Collagen can selectively trigger a platelet secretory phenotype via glycoprotein VI. PLoS ONE 9, e104712 (2014).

    Google Scholar 

  145. Inoue, O. et al. Laminin stimulates spreading of platelets through integrin α6β1-dependent activation of GPVI. Blood 107, 1405–1412 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Stack, J. R. et al. Soluble glycoprotein VI, a specific marker of platelet activation is increased in the plasma of subjects with seropositive rheumatoid arthritis. PLoS ONE 12, e0188027 (2017).

    PubMed  PubMed Central  Google Scholar 

  147. Alshehri, O. M. et al. Fibrin activates GPVI in human and mouse platelets. Blood 126, 1601–1608 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Kell, D. B. & Pretorius, E. The simultaneous occurrence of both hypercoagulability and hypofibrinolysis in blood and serum during systemic inflammation, and the roles of iron and fibrin(ogen). Integr. Biol. 7, 24–52 (2015).

    CAS  Google Scholar 

  149. So, A. K. et al. Arthritis is linked to local and systemic activation of coagulation and fibrinolysis pathways. J. Thromb. Haemost. 1, 2510–2515 (2003).

    CAS  PubMed  Google Scholar 

  150. Rooney, T. et al. Levels of plasma fibrinogen are elevated in well-controlled rheumatoid arthritis. Rheumatology 50, 1458–1465 (2011).

    CAS  PubMed  Google Scholar 

  151. Induruwa, I. et al. Platelet collagen receptor glycoprotein VI-dimer recognizes fibrinogen and fibrin through their D-domains, contributing to platelet adhesion and activation during thrombus formation. J. Thromb. Haemost. 16, 389–404 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Seizer, P. et al. EMMPRIN (CD147) is a novel receptor for platelet GPVI and mediates platelet rolling via GPVI-EMMPRIN interaction. Thromb. Haemost. 101, 682–686 (2009).

    Google Scholar 

  153. Wang, C. H. et al. CD147 induces angiogenesis through a vascular endothelial growth factor and hypoxia-inducible transcription factor 1α–mediated pathway in rheumatoid arthritis. Arthritis Rheum. 64, 1818–1827 (2012).

    CAS  PubMed  Google Scholar 

  154. Cloutier, N. et al. Platelets can enhance vascular permeability. Blood 120, 1334–1343 (2012).

    CAS  PubMed  Google Scholar 

  155. Oliver, K. H., Duvernay, M. T., Hamm, H. E. & Carneiro, A. M. Loss of serotonin transporter function alters ADP-mediated glycoprotein αIIbβ3 activation through dysregulation of the 5-HT2A receptor. J. Biol. Chem. 291, 20210–20219 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Carneiro, A. M., Cook, E. H., Murphy, D. L. & Blakely, R. D. Interactions between integrin αIIbβ3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans. J. Clin. Invest. 118, 1544–1552 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Duerschmied, D. et al. Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood 121, 1008–1015 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 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 109, 3139–3146 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Bernardes, M. et al. Serum serotonin levels and bone in rheumatoid arthritis patients. Rheumatol. Int. 37, 1891–1898 (2017).

    CAS  PubMed  Google Scholar 

  160. Lopez-Vilchez, I., Diaz-Ricart, M., White, J. G., Escolar, G. & Galan, A. M. Serotonin enhances platelet procoagulant properties and their activation induced during platelet tissue factor uptake. Cardiovasc. Res. 84, 309–316 (2009).

    CAS  PubMed  Google Scholar 

  161. Okamoto, K. et al. The role of peripheral 5HT2A and 5HT1A receptors on the orofacial formalin test in rats with persistent temporomandibular joint inflammation. Neuroscience 130, 465–474 (2005).

    CAS  PubMed  Google Scholar 

  162. Kling, A., Rantapaa-Dahlqvist, S., Stenlund, H. & Mjorndal, T. Decreased density of serotonin 5-HT2A receptors in rheumatoid arthritis. Ann. Rheum. Dis. 65, 816–819 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Snir, O. et al. Genetic variation in the serotonin receptor gene affects immune responses in rheumatoid arthritis. Genes Immun. 14, 83–89 (2013).

    CAS  PubMed  Google Scholar 

  164. D’Atri, L. P. & Schattner, M. Platelet Toll-like receptors in thromboinflammation. Front. Biosci. 22, 1867–1883 (2017).

    Google Scholar 

  165. Panigrahi, S. et al. Engagement of platelet Toll-like receptor 9 by novel endogenous ligands promotes platelet hyperreactivity and thrombosis. Circ. Res. 112, 103–112 (2013).

    CAS  PubMed  Google Scholar 

  166. Koupenova, M. et al. Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis. Blood 124, 791–802 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Anabel, A. S. et al. Human platelets express Toll-like receptor 3 and respond to poly I:C. Hum. Immunol. 75, 1244–1251 (2014).

    CAS  PubMed  Google Scholar 

  168. Cognasse, F. et al. Evidence of Toll-like receptor molecules on human platelets. Immunol. Cell Biol. 83, 196–198 (2005).

    CAS  PubMed  Google Scholar 

  169. Shiraki, R. et al. Expression of Toll-like receptors on human platelets. Thromb. Res. 113, 379–385 (2004).

    CAS  PubMed  Google Scholar 

  170. Koupenova, M. et al. Sex differences in platelet toll-like receptors and their association with cardiovascular risk factors. Arterioscler. Thromb. Vasc. Biol. 35, 1030–1037 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Molteni, M., Gemma, S. & Rossetti, C. The role of Toll-Like Receptor 4 in infectious and noninfectious inflammation. Mediators Inflamm. 2016, 6978936 (2016).

    PubMed  PubMed Central  Google Scholar 

  172. Akira, S. & Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499–511 (2004).

    CAS  PubMed  Google Scholar 

  173. Zhang, G. et al. Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J. Immunol. 182, 7997–8004 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Vogel, S. et al. Platelet-derived HMGB1 is a critical mediator of thrombosis. J. Clin. Invest. 125, 4638–4654 (2015).

    PubMed  PubMed Central  Google Scholar 

  175. Rivadeneyra, L. et al. Regulation of platelet responses triggered by Toll-like receptor 2 and 4 ligands is another non-genomic role of nuclear factor-kappaB. Thromb. Res. 133, 235–243 (2014).

    CAS  PubMed  Google Scholar 

  176. Vieira-de-Abreu, A., Campbell, R. A., Weyrich, A. S. & Zimmerman, G. A. Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. Semin. Immunopathol. 34, 5–30 (2012).

    CAS  PubMed  Google Scholar 

  177. Shashkin, P. N., Brown, G. T., Ghosh, A., Marathe, G. K. & McIntyre, T. M. Lipopolysaccharide is a direct agonist for platelet RNA splicing. J. Immunol. 181, 3495–3502 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Rondina, M. T. et al. The septic milieu triggers expression of spliced tissue factor mRNA in human platelets. J. Thromb. Haemost. 9, 748–758 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Cheng, N., He, R., Tian, J., Ye, P. P. & Ye, R. D. Cutting edge: TLR2 is a functional receptor for acute-phase serum amyloid A. J. Immunol. 181, 22–26 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Blair, P. et al. Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase. Circ. Res. 104, 346–354 (2009).

    CAS  PubMed  Google Scholar 

  181. Huang, Q. Q. & Pope, R. M. The role of Toll-like receptors in rheumatoid arthritis. Curr. Rheumatol. Rep. 11, 357–364 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Iwahashi, M. et al. Expression of Toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis. Arthritis Rheum. 50, 1457–1467 (2004).

    CAS  PubMed  Google Scholar 

  183. Radstake, T. R. et al. Expression of Toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma. Arthritis Rheum. 50, 3856–3865 (2004).

    CAS  PubMed  Google Scholar 

  184. Roelofs, M. F. et al. The expression of Toll-like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of Toll-like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells. Arthritis Rheum. 52, 2313–2322 (2005).

    CAS  PubMed  Google Scholar 

  185. Taniguchi, N. et al. High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum. 48, 971–981 (2003).

    CAS  PubMed  Google Scholar 

  186. Raijmakers, R. et al. Elevated levels of fibrinogen-derived endogenous citrullinated peptides in synovial fluid of rheumatoid arthritis patients. Arthritis Res. Ther. 14, R114 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Kimura, E. et al. Identification of citrullinated cellular fibronectin in synovial fluid from patients with rheumatoid arthritis. Mod. Rheumatol. 24, 766–769 (2014).

    CAS  PubMed  Google Scholar 

  188. Chang, X., Yamada, R. & Yamamoto, K. Inhibition of antithrombin by hyaluronic acid may be involved in the pathogenesis of rheumatoid arthritis. Arthritis Res. Ther. 7, R268–R273 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Brentano, F., Kyburz, D. & Gay, S. Toll-like receptors and rheumatoid arthritis. Methods Mol. Biol. 517, 329–343 (2009).

    CAS  PubMed  Google Scholar 

  190. Kim, K. W. et al. Human rheumatoid synovial fibroblasts promote osteoclastogenic activity by activating RANKL via TLR-2 and TLR-4 activation. Immunol. Lett. 110, 54–64 (2007).

    CAS  PubMed  Google Scholar 

  191. Fischer, A. et al. The involvement of Toll-like receptor 9 in the pathogenesis of erosive autoimmune arthritis. J. Cell. Mol. Med. 22, 4399–4409 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Sacre, S. M. et al. The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis. Am. J. Pathol. 170, 518–525 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Ospelt, C. et al. Overexpression of Toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: Toll-like receptor expression in early and longstanding arthritis. Arthritis Rheum. 58, 3684–3692 (2008).

    CAS  PubMed  Google Scholar 

  194. Israels, S. J. & McMillan-Ward, E. M. CD63 modulates spreading and tyrosine phosphorylation of platelets on immobilized fibrinogen. Thromb. Haemost. 93, 311–318 (2005).

    CAS  PubMed  Google Scholar 

  195. Israels, S. J., McMillan-Ward, E. M., Easton, J., Robertson, C. & McNicol, A. CD63 associates with the alphaIIb beta3 integrin-CD9 complex on the surface of activated platelets. Thromb. Haemost. 85, 134–141 (2001).

    CAS  PubMed  Google Scholar 

  196. Arntz, O. J. et al. Rheumatoid arthritis patients with circulating extracellular vesicles positive for IgM rheumatoid factor have higher disease activity. Front. Immunol. 9, 2388 (2018).

    PubMed  PubMed Central  Google Scholar 

  197. Marjoram, R. J. et al. Suboptimal activation of protease-activated receptors enhances α2β1 integrin-mediated platelet adhesion to collagen. J. Biol. Chem. 284, 34640–34647 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Russell, F. A. & McDougall, J. J. Proteinase activated receptor (PAR) involvement in mediating arthritis pain and inflammation. Inflamm Res. 58, 119–126 (2009).

    CAS  PubMed  Google Scholar 

  199. Duvernay, M., Young, S., Gailani, D., Schoenecker, J. & Hamm, H. E. Protease-activated receptor (PAR) 1 and PAR4 differentially regulate factor V expression from human platelets. Mol. Pharmacol. 83, 781–792 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Trumel, C. et al. A key role of adenosine diphosphate in the irreversible platelet aggregation induced by the PAR1-activating peptide through the late activation of phosphoinositide 3-kinase. Blood 94, 4156–4165 (1999).

    CAS  PubMed  Google Scholar 

  201. Steinhoff, M. et al. Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr. Rev. 26, 1–43 (2005).

    CAS  PubMed  Google Scholar 

  202. Fender, A. C., Rauch, B. H., Geisler, T. & Schror, K. Protease-activated receptor PAR-4: An inducible switch between thrombosis and vascular inflammation? Thromb. Haemost. 117, 2013–2025 (2017).

    PubMed  Google Scholar 

  203. Weinberg, J. B., Pippen, A. M. M. & Greenberg, C. S. Extravascular fibrin formation and dissolution in synovial tissue of patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum. 34, 996–1005 (1991).

    Google Scholar 

  204. Stephens, G. et al. Platelet activation induces metalloproteinase-dependent GP VI cleavage to down-regulate platelet reactivity to collagen. Blood 105, 186–191 (2005).

    CAS  PubMed  Google Scholar 

  205. Ramachandran, R., Noorbakhsh, F., Defea, K. & Hollenberg, M. D. Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat. Rev. Drug Discov. 11, 69–86 (2012).

    CAS  PubMed  Google Scholar 

  206. Gachet, C. ADP receptors of platelets and their inhibition. Thromb. Haemost. 86, 222–232 (2001).

    CAS  PubMed  Google Scholar 

  207. Jung, S. M. & Moroi, M. Platelet collagen receptor integrin α2β1 activation involves differential participation of ADP-receptor subtypes P2Y1 and P2Y12 but not intracellular calcium change. Eur. J. Biochem. 268, 3513–3522 (2001).

    CAS  PubMed  Google Scholar 

  208. Koessler, J. et al. The role of agonist-induced activation and inhibition for the regulation of purinergic receptor expression in human platelets. Thromb. Res. 168, 40–46 (2018).

    CAS  PubMed  Google Scholar 

  209. Becker, L. V. et al. Activities of enzymes that hydrolyze adenine nucleotides in platelets from patients with rheumatoid arthritis. Clin. Biochem. 43, 1096–1100 (2010).

    CAS  PubMed  Google Scholar 

  210. Aburima, A. et al. cAMP signaling regulates platelet myosin light chain (MLC) phosphorylation and shape change through targeting the RhoA-Rho kinase-MLC phosphatase signaling pathway. Blood 122, 3533–3545 (2013).

    CAS  PubMed  Google Scholar 

  211. Aslan, J. E. & McCarty, O. J. Rho GTPases in platelet function. J. Thromb. Haemost. 11, 35–46 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Ajeganova, S. et al. Longitudinal levels of apolipoproteins and antibodies against phosphorylcholine are independently associated with carotid artery atherosclerosis 5 years after rheumatoid arthritis onset—a prospective cohort study. Rheumatology 50, 1785–1793 (2011).

    CAS  PubMed  Google Scholar 

  213. Szekanecz, Z., Vegvari, A., Szabo, Z. & Koch, A. E. Chemokines and chemokine receptors in arthritis. Front. Biosci. (Schol. Ed.) 2, 153–167 (2010).

    Google Scholar 

  214. Koopman, F. A. et al. Autonomic dysfunction precedes development of rheumatoid arthritis: a prospective cohort study. EBioMedicine 6, 231–237 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Bahlas, S. et al. Rapid immunoprofiling of cytokines, chemokines and growth factors in patients with active rheumatoid arthritis using Luminex Multiple Analyte Profiling technology for precision medicine. Clin. Exp. Rheumatol. 27, 112–119 (2018).

    Google Scholar 

  216. Zhang, Y. et al. A novel circulating miRNA-based model predicts the response to tripterysium glycosides tablets: moving toward model-based precision medicine in rheumatoid arthritis. Front. Pharmacol. 9, 378 (2018).

    PubMed  PubMed Central  Google Scholar 

  217. Ragouzeos, D. et al. “Am I OK?” using human centered design to empower rheumatoid arthritis patients through patient reported outcomes. Patient Educ. Couns. https://doi.org/10.1016/j.pec.2018.10.016 (2018).

    Article  PubMed  Google Scholar 

  218. Machlus, K. R. & Italiano, J. E. Jr. The incredible journey: from megakaryocyte development to platelet formation. J. Cell Biol. 201, 785–796 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Lefrancais, E. et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature 544, 105–109 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Jin, J. & Kunapuli, S. P. Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation. PNAS 95, 8070–8074 (1998).

    CAS  PubMed  Google Scholar 

  221. Shen, Y. et al. Requirement of leucine-rich repeats of glycoprotein (GP) Ibα for shear-dependent and static binding of von Willebrand factor to the platelet membrane GP Ib-IX-V complex. Blood 95, 903–910 (2000).

    CAS  PubMed  Google Scholar 

  222. Bester, J. & Pretorius, E. Effects of IL-1β, IL-6 and IL-8 on erythrocytes, platelets and clot viscoelasticity. Sci. Rep. 6, 32188 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The work of the authors was funded by the South African Medical Research Council and the National Research Foundation (South Africa; grant number N00345 to E.P.).

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A search for original articles published between 1984 and 2018 without language restriction was performed in PubMed, MEDLINE, Google Scholar and Scopus. The search terms used were “platelet rheumatoid arthritis”, “platelet ligands”, “platelet microparticle”, “platelet uptake and secretion”, “platelet receptors”, “platelet signalling pathways” and “immune functions”. All articles identified were reviewed manually for eligibility.

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Nature Reviews Rheumatology thanks J. Semple and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Physiology, Faculty of Health Science, University of Pretoria, Pretoria, South Africa

    Oore-ofe Olumuyiwa-Akeredolu & Prashilla Soma

  2. Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa

    Martin J. Page & Etheresia Pretorius

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O.O.-A. researched data for the article. O.O.-A. and E.P. provided substantial contributions to discussion of content. O.O.-A., M.J.P. and E.P. wrote the article and all authors reviewed and/or edited the manuscript before submission.

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Glossary

Plateletcrit

A measure of the number of platelets present in a blood fraction.

Platelet distribution width

A blood parameter that measures the variability in platelet size distribution.

Mean platelet volume

A measure of the average size of platelets within a blood sample.

Platelet spreading

An indicator of cellular activation that involves reorganization of the actin cytoskeleton to extend filopodia and lamellipodia, thereby converting platelets from biconcave to amorphous cells.

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Olumuyiwa-Akeredolu, Oo., Page, M.J., Soma, P. et al. Platelets: emerging facilitators of cellular crosstalk in rheumatoid arthritis. Nat Rev Rheumatol 15, 237–248 (2019). https://doi.org/10.1038/s41584-019-0187-9

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