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Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):454-463
Leukocyte Biology
Alternative activation of human macrophages enhances tissue factor expression and pro- duction of extracellular vesicles
Philipp J. Hohensinner,1,2 Julia Mayer,1 Julia Kirchbacher,1 Julia Kral-Pointner,1,2
Barbara Thaler,1 Christoph Kaun,1 Lena Hell,3 Patrick Haider,1 Marion
Mussbacher,4 Johannes A. Schmid,4 Stefan Stojkovic,1 Svitlana Demyanets,1,5
Michael B. Fischer,6,7 Kurt Huber,2,8,9 Katharina Wöran,10 Christian
Hengstenberg,1 Walter S. Speidl,1 Rudolf Oehler,11 Ingrid Pabinger3 and Johann Wojta1,2,12
1Department of Internal Medicine II/Cardiology, Medical University of Vienna, Vienna; 2Ludwig Boltzmann Institute for Cardiovascular Research, Vienna; 3Department of Internal Medicine I, Medical University of Vienna, Vienna; 4Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna; 5Department of Laboratory Medicine, Medical University of Vienna, Vienna; 6Clinic for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna; 7Department for Health Science and Biomedicine, Danube University Krems, Krems; 83rd Medical Department, Wilhelminenhospital, Vienna; 9Medical Faculty, Sigmund Freud University, Vienna; 10Department of Pathology, Medical University of Vienna, Vienna; 11Department of Surgery, Medical University of Vienna, Vienna and 12Core Facilities, Medical University of Vienna, Vienna, Austria
ABSTRACT
Macrophages are versatile cells that can be polarized by the tissue environment to fulfill required needs. Proinflammatory polariza- tion is associated with increased tissue degradation and propaga- tion of inflammation whereas alternative polarization within a Th2 cytokine environment is associated with wound healing and angiogenesis. To under- stand whether polarization of macrophages can lead to a procoagulant macrophage subset we polarized human monocyte-derived macrophages to proinflammatory and alternative activation states. Alternative polarization with interleukin-4 and interleukin-13 led to a macrophage phenotype char- acterized by increased tissue factor (TF) production and release and by an increase in extracellular vesicle production. In addition, TF activity was enhanced in extracellular vesicles of alternatively polarized macrophages. This TF induction was dependent on signal transducer and activator of tran- scription-6 signaling and poly ADP ribose polymerase activity. In contrast to monocytes, human macrophages did not show increased TF expression upon stimulation with lipopolysaccharide and interferon-γ. Previous polar- ization to either a proinflammatory or an alternative activation subset did not change the subsequent stimulation of TF. The inability of proinflamma- tory activated macrophages to respond to lipopolysaccharide and interferon- γ with an increase in TF production seemed to be due to an increase in TF promoter methylation and was reversible when these macrophages were treated with a demethylating agent. In conclusion, we provide evidence that proinflammatory polarization of macrophages does not lead to enhanced procoagulatory function, whereas alternative polarization of macrophages leads to an increased expression of TF and increased production of TF-bear- ing extracellular vesicles by these cells suggesting a procoagulatory pheno- type of alternatively polarized macrophages.
Introduction
Macrophages are cells of the innate immune system which play numerous and vastly different functions within the body. Macrophages reside in all tissues of the body and each population of macrophages within a tissue can take on specialized functions that are tuned to the developmental and functional requirements of that
Correspondence:
JOHANN WOJTA
johann.wojta@meduniwien.ac.at
Received: February 26, 2019. Accepted: January 23, 2020. Pre-published: January 23, 2020.
https://doi.org/10.3324/haematol.2019.220210
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