Page 148 - 2021_02-Haematologica-web

P.J. Hohensinner et al.
already back in 1989, Wilcox et al. demonstrated that not all TF was associated with cells,57 a notion our data from both atherosclerotic tissue and cancer tissue would sup- port. Within the atherosclerotic environment macrophages are polarized into different subsets. Both proinflammatory and alternatively activated macrophages were reported to coexist within this environment.58 Our data demonstrate that both proinflammatory CD80+ macrophages as well as alternatively activated CD206+ macrophages are sources for TF. Nonetheless, CD206+ macrophages are associated with an increased production of TF within the atheroscle- rotic lesion, supporting our in vitro data showing induction of TF through alternative activation.
In conclusion, we provide new evidence that alternative polarization of macrophages leads to a procoagulatory phenotype through the expression of TF and the produc- tion of TF-containing extracellular vesicles and might change overall cellular behavior including migratory prefer- ences. Together with our previously published results showing that alternatively activated macrophages express
increased levels of the antifibrinolytic serpin plasminogen activator inhibitor-1,7 our results suggest that alternatively polarized macrophages support thrombus formation and suppress thrombolysis59 and thus represent a novel cellular mediator linking macrophages and thrombosis in patholo- gies characterized by these events.
Disclosures
This work was supported by a grant from the FWF, the Austrian Science Fund to JW (SFB-54).
Contributions
PJH, JM, JK, JKP, BT, CK, LH, PH, MM, SS and KW per- formed the research; JKPWSS analyzed the data; PJH and JW wrote the manuscript; JAS, SD, MBF, KH, CH, RO, IP and JW supervised the study.
Acknowledgments
This work was supported by a grant from the FWF, the Austrian Science Fund, to IP, JS and JW (SFB-54).
References
1. Glass CK. Genetic and genomic approaches to understanding macrophage identity and function. Arterioscler Thromb Vasc Biol. 2015;35(4):755-762.
2. Cybulsky MI, Cheong C, Robbins CS. Macrophages and dendritic cells: partners in atherogenesis. Circ Res. 2016;118(4):637-652.
3. Murray PJ, Wynn TA. Protective and patho- genic functions of macrophage subsets. Nat Rev Immunol. 2011;11(11):723-737.
4. Murray PJ. Macrophage polarization. Annu Rev Physiol. 2017;79:541-66.
5. Lech M, Anders HJ. Macrophages and fibro- sis: how resident and infiltrating mononu- clear phagocytes orchestrate all phases of tissue injury and repair. Biochim Biophys Acta. 2013;1832(7):989-997.
6. Porta C, Rimoldi M, Raes G, et al. Tolerance and M2 (alternative) macrophage polariza- tion are related processes orchestrated by p50 nuclear factor kappaB. Proc Natl Acad Sci U S A. 2009;106(35):14978-14983.
7. Hohensinner PJ, Baumgartner J, Kral- Pointner JB, et al. PAI-1 (plasminogen activa- tor inhibitor-1) expression renders alterna- tively activated human macrophages prote- olytically quiescent. Arterioscler Thromb Vasc Biol. 2017;37 (10):1913-1922.
8. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor- associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549-555.
9. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787-795.
10. Grover SP, Mackman N. Tissue factor: an essential mdiator of hemostasis and trigger of thrombosis. Arterioscler Thromb Vasc Biol. 2018;38(4):709-725.
11. Pawlinski R, Wang JG, Owens AP 3rd, et al. Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cas- cade in endotoxemic mice. Blood. 2010;116(5):806-814.
12.Berckmans RJ, Sturk A, van Tienen LM, Schaap MC, Nieuwland R. Cell-derived vesicles exposing coagulant tissue factor in saliva. Blood. 2011;117(11):3172-3180.
13.Gardiner C, Harrison P, Belting M, et al. Extracellular vesicles, tissue factor, cancer and thrombosis - discussion themes of the ISEV 2014 Educational Day. J Extracell Vesicles. 2015;4:26901.
14. Butler JT, Abdelhamed S, Kurre P. Extracellular vesicles in the hematopoietic microenvironment. Haematologica. 2018; 103(3):382-394.
15. Ettelaie C, Collier ME, Maraveyas A, Ettelaie R. Characterization of physical properties of tissue factor-containing microvesicles and a comparison of ultracen- trifuge-based recovery procedures. J Extracell Vesicles. 2014;3.
16. Yanez-Mo M, Siljander PR, Andreu Z, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015;4:27066.
17. Tripisciano C, Weiss R, Eichhorn T, et al. Different potential of extracellular vesicles to support thrombin generation: contribu- tions of phosphatidylserine, tissue factor, and cellular origin. Sci Rep. 2017;7(1):6522.
18. Hohensinner PJ, Baumgartner J, Ebenbauer B, et al. Statin treatment reduces matrix degradation capacity of proinflammatory polarized macrophages. Vascul Pharmacol. 2018;110:49-54.
19. Thaler B, Hohensinner PJ, Krychtiuk KA, et al. Differential in vivo activation of mono- cyte subsets during low-grade inflammation through experimental endotoxemia in humans. Sci Rep. 2016;6:30162.
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.
21. Hohensinner PJ, Takacs N, Kaun C, et al. Urokinase plasminogen activator protects cardiac myocytes from oxidative damage and apoptosis via hOGG1 induction. Apoptosis. 2017;22(8):1048-1055.
22. Dorfleutner A, Hintermann E, Tarui T, Takada Y, Ruf W. Cross-talk of integrin alpha3beta1 and tissue factor in cell migra- tion. Mol Biol Cell. 2004;15(10):4416-4425.
23. Brueckner B, Garcia Boy R, Siedlecki P, et al. Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer
Res. 2005;65(14):6305-6311.
24. Hamilton JA. Colony-stimulating factors in
inflammation and autoimmunity. Nat Rev
Immunol. 2008;8(7):533-544.
25. Hamilton TA, Zhao C, Pavicic PG, Jr., Datta
S. Myeloid colony-stimulating factors as regulators of macrophage polarization. Front Immunol. 2014;5:554.
26. Kocaturk B, Versteeg HH. Tissue factor-inte- grin interactions in cancer and thrombosis: every Jack has his Jill. J Thromb Haemost. 2013;11 Suppl 1:285-293.
27. Rothmeier AS, Marchese P, Langer F, et al. Tissue factor prothrombotic activity is regu- lated by integrin-arf6 trafficking. Arterioscler Thromb Vasc Biol. 2017;37(7): 1323-1331.
28. Rothmeier AS, Marchese P, Petrich BG, et al. Caspase-1-mediated pathway promotes generation of thromboinflammatory microparticles. J Clin Invest. 2015;125 (4):1471-1484.
29. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496 (7446):445-455.
30. Hoeksema MA, Glass CK. Nature and nur- ture of tissue-specific macrophage pheno- types. Atherosclerosis. 2019;281:159-167.
31. Czimmerer Z, Daniel B, Horvath A, et al. The transcription factor STAT6 mediates direct repression of inflammatory enhancers and lmits activation of alternatively polar- ized macrophages. Immunity. 2018;48(1): 75-90 e6.
32. Qiao Y, Kang K, Giannopoulou E, Fang C, Ivashkiv LB. IFN-γ induces histone 3 lysine 27 trimethylation in a small subset of pro- moters to stably silence gene expression in human macrophages. Cell Rep. 2016;16(12): 3121-3129.
33. Van den Bossche J, Baardman J, Otto NA, et al. Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Rep. 2016;17(3):684-696.
34. Mackman N, Brand K, Edgington TS. Lipopolysaccharide-mediated transcription- al activation of the human tissue factor gene in THP-1 monocytic cells requires both acti- vator protein 1 and nuclear factor kappa B binding sites. J Exp Med. 1991;174(6):1517- 1526.
462
haematologica | 2021; 106(2)