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CC BY-NC-ND 4.0 · Thromb Haemost 2019; 119(09): 1394-1402
DOI: 10.1055/s-0039-1692219
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Protease-Activated Receptors 1 and 3 are Differentially Expressed on Human Monocyte Subsets and are Upregulated by Lipopolysaccharide Ex Vivo and In Vivo

Barbara Thaler
1   Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Philipp J. Hohensinner
1   Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Johanna Baumgartner
1   Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Patrick Haider
1   Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Konstantin A. Krychtiuk
1   Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Christian Schörgenhofer
2   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
,
Bernd Jilma
2   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
,
Lena Hell
3   Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
,
Michael B. Fischer
4   Clinic for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
5   Department for Health Science and Biomedicine, Danube University Krems, Krems, Austria
,
Kurt Huber
6   3rd Medical Department for Cardiology and Emergency Medicine, Wilhelminen Hospital, Vienna, Austria
,
Christian Hengstenberg
1   Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Walter S. Speidl
1   Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Johann Wojta
1   Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
7   Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria
8   Core Facilities, Medical University of Vienna, Vienna, Austria
› Author Affiliations Funding This project was funded by a grant of the Austrian Science Fund FWF (SFB-54) to J.W. and W.S.S.
Further Information

Publication History

17 November 2018

29 April 2019

Publication Date:
10 July 2019 (online)

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Abstract

Monocytes are activated in inflammatory conditions via a variety of cytokine receptors as well as in a procoagulatory setting through thrombin, acting upon protease-activated receptors (PARs). This study investigated the expression pattern of PAR1 and PAR3 on human monocyte subsets. Furthermore, a possible regulation of the expression of PAR1 and PAR3 in these cells by inflammatory activation were studied. CD16+ monocytes showed significantly higher levels of PAR1 and PAR3 as compared with CD16− monocytes. Ex vivo treatment of whole blood with lipopolysaccharide (LPS) increased PAR1 and PAR3 messenger ribonucleic acid (mRNA) in human monocytes. In addition, increase of PAR1 was seen in all three subsets upon LPS treatment, whereas PAR3 increased significantly only in CD16− monocytes and nonclassical CD16+ monocytes. Protein levels of PAR1 and PAR3 significantly increased on monocytes in vivo in human endotoxemia 1 hour after LPS infusion. PAR1 increased significantly in CD16− monocytes and nonclassical CD16+ monocytes. In this in vivo model, PAR3 was also significantly elevated in CD16− monocytes and increased slightly albeit not significantly in CD16+ monocytes. Endotoxemia increased plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) expression in monocytes in humans. Pretreatment of healthy volunteers with the PAR1 antagonist vorapaxar blocked the increase in PAI-1 but not the increase in TF. We here provide new evidence for a critical role for monocytes as cellular mediators that contribute to the activation of coagulation in diseases characterized by an inflammatory state.

Keywords

monocyte subsets - protease-activated receptors - low-grade inflammation - coagulation
 

  • References

  • 1 Akdis M, Aab A, Altunbulakli C. , et al. Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases. J Allergy Clin Immunol 2016; 138 (04) 984-1010
    CrossrefPubMedGoogle Scholar
  • 2 Borissoff JI, Spronk HMH, Heeneman S, ten Cate H. Is thrombin a key player in the ‘coagulation-atherogenesis’ maze?. Cardiovasc Res 2009; 82 (03) 392-403
    CrossrefPubMedGoogle Scholar
  • 3 Hollenberg MD, Mihara K, Polley D. , et al. Biased signalling and proteinase-activated receptors (PARs): targeting inflammatory disease. Br J Pharmacol 2014; 171 (05) 1180-1194
    CrossrefPubMedGoogle Scholar
  • 4 Isermann B. Homeostatic effects of coagulation protease-dependent signaling and protease activated receptors. J Thromb Haemost 2017; 15 (07) 1273-1284
    CrossrefPubMedGoogle Scholar
  • 5 Gieseler F, Ungefroren H, Settmacher U, Hollenberg MD, Kaufmann R. Proteinase-activated receptors (PARs) - focus on receptor-receptor-interactions and their physiological and pathophysiological impact. Cell Commun Signal 2013; 11: 86
    CrossrefPubMedGoogle Scholar
  • 6 Nieman MT. Protease-activated receptors in hemostasis. Blood 2016; 128 (02) 169-177
    PubMedGoogle Scholar
  • 7 Colognato R, Slupsky JR, Jendrach M, Burysek L, Syrovets T, Simmet T. Differential expression and regulation of protease-activated receptors in human peripheral monocytes and monocyte-derived antigen-presenting cells. Blood 2003; 102 (07) 2645-2652
    CrossrefPubMedGoogle Scholar
  • 8 Ziegler-Heitbrock L, Ancuta P, Crowe S. , et al. Nomenclature of monocytes and dendritic cells in blood. Blood 2010; 116 (16) e74-e80
    CrossrefPubMedGoogle Scholar
  • 9 Weber C, Shantsila E, Hristov M. , et al. Role and analysis of monocyte subsets in cardiovascular disease. Joint consensus document of the European Society of Cardiology (ESC) Working Groups “Atherosclerosis & Vascular Biology” and “Thrombosis”. Thromb Haemost 2016; 116 (04) 626-637
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Hristov M, Heine GH. Monocyte subsets in atherosclerosis. Hamostaseologie 2015; 35 (02) 105-112
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Poitou C, Dalmas E, Renovato M. , et al. CD14dimCD16+ and CD14+CD16+ monocytes in obesity and during weight loss: relationships with fat mass and subclinical atherosclerosis. Arterioscler Thromb Vasc Biol 2011; 31 (10) 2322-2330
    CrossrefPubMedGoogle Scholar
  • 12 Weldon AJ, Moldovan I, Cabling MG. , et al. Surface APRIL is elevated on myeloid cells and is associated with disease activity in patients with rheumatoid arthritis. J Rheumatol 2015; 42 (05) 749-759
    PubMedGoogle Scholar
  • 13 Grip O, Bredberg A, Lindgren S, Henriksson G. Increased subpopulations of CD16(+) and CD56(+) blood monocytes in patients with active Crohn's disease. Inflamm Bowel Dis 2007; 13 (05) 566-572
    CrossrefPubMedGoogle Scholar
  • 14 Mukherjee R, Kanti Barman P, Kumar Thatoi P, Tripathy R, Kumar Das B, Ravindran B. Non-classical monocytes display inflammatory features: validation in sepsis and systemic lupus erythematous. Sci Rep 2015; 5: 13886
    CrossrefPubMedGoogle Scholar
  • 15 Krychtiuk KA, Lenz M, Koller L. , et al. Monocyte subset distribution is associated with mortality in critically ill patients. Thromb Haemost 2016; 116 (05) 949-957
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Thaler B, Hohensinner PJ, Krychtiuk KA. , et al. Differential in vivo activation of monocyte subsets during low-grade inflammation through experimental endotoxemia in humans. Sci Rep 2016; 6: 30162
    CrossrefPubMedGoogle Scholar
  • 17 Jilma-Stohlawetz P, Kliegel T, Kantner-Schlifke I, Strasser-Marsik C, Mayr FB, Jilma B. Upregulation of cytokine mRNA in circulating leukocytes during human endotoxemia. Eur Cytokine Netw 2017; 28 (01) 19-26
    PubMedGoogle Scholar
  • 18 Mayr FB, Spiel AO, Leitner JM. , et al. Duffy antigen modifies the chemokine response in human endotoxemia. Crit Care Med 2008; 36 (01) 159-165
    CrossrefPubMedGoogle Scholar
  • 19 Stojkovic S, Thulin Å, Hell L. , et al. IL-33 stimulates the release of procoagulant microvesicles from human monocytes and differentially increases tissue factor in human monocyte subsets. Thromb Haemost 2017; 117 (07) 1379-1390
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Khorana AA, Francis CW, Menzies KE. , et al. Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer. J Thromb Haemost 2008; 6 (11) 1983-1985
    CrossrefPubMedGoogle Scholar
  • 21 Schoergenhofer C, Schwameis M, Gelbenegger G. , et al. Inhibition of protease-activated receptor (PAR1) reduces activation of the endothelium, coagulation, fibrinolysis and inflammation during human endotoxemia. Thromb Haemost 2018; 118 (07) 1176-1184
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Grover SP, Mackman N. Tissue factor: an essential mediator of hemostasis and trigger of thrombosis. Arterioscler Thromb Vasc Biol 2018; 38 (04) 709-725
    CrossrefPubMedGoogle Scholar
  • 23 Jung RG, Simard T, Labinaz A. , et al. Role of plasminogen activator inhibitor-1 in coronary pathophysiology. Thromb Res 2018; 164: 54-62
    CrossrefPubMedGoogle Scholar
  • 24 Hamilton JA, Whitty GA, Wojta J, Gallichio M, McGrath K, Ianches G. Regulation of plasminogen activator inhibitor-1 levels in human monocytes. Cell Immunol 1993; 152 (01) 7-17
    CrossrefPubMedGoogle Scholar
  • 25 Mackman N. Regulation of the tissue factor gene. FASEB J 1995; 9 (10) 883-889
    CrossrefPubMedGoogle Scholar
  • 26 Derhaschnig U, Bergmair D, Marsik C, Schlifke I, Wijdenes J, Jilma B. Effect of interleukin-6 blockade on tissue factor-induced coagulation in human endotoxemia. Crit Care Med 2004; 32 (05) 1136-1140
    CrossrefPubMedGoogle Scholar
  • 27 Hamilton JA, Whitty GA, Stanton H. , et al. Macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor stimulate the synthesis of plasminogen-activator inhibitors by human monocytes. Blood 1993; 82 (12) 3616-3621
    CrossrefPubMedGoogle Scholar
  • 28 Gregory SA, Morrissey JH, Edgington TS. Regulation of tissue factor gene expression in the monocyte procoagulant response to endotoxin. Mol Cell Biol 1989; 9 (06) 2752-2755
    CrossrefPubMedGoogle Scholar
  • 29 Posma JJN, Posthuma JJ, Spronk HMH. Coagulation and non-coagulation effects of thrombin. J Thromb Haemost 2016; 14 (10) 1908-1916
    CrossrefPubMedGoogle Scholar
  • 30 Egorina EM, Sovershaev MA, Hansen J-B. The role of tissue factor in systemic inflammatory response syndrome. Blood Coagul Fibrinolysis 2011; 22 (06) 451-456
    CrossrefPubMedGoogle Scholar
  • 31 Tricoci P, Huang Z, Held C. , et al; TRACER Investigators. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012; 366 (01) 20-33
    CrossrefPubMedGoogle Scholar