PAI-1 (Plasminogen Activator Inhibitor-1) Expression Renders Alternatively Activated Human Macrophages Proteolytically Quiescent
| Autor: | Walter S. Speidl, Konstantin Doberer, Philipp J. Hohensinner, Gernot Schabbauer, Barbara Thaler, Svitlana Demyanets, Michael B. Fischer, Pavel Uhrin, Johanna Baumgartner, Johann Wojta, B. Ebenbauer, Stefan Stojkovic, Kurt Huber, Julia B. Kral-Pointner |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
serine proteases Adipose tissue macrophages Macrophage-activating factor Stimulation Matrix metalloproteinase Receptors Urokinase Plasminogen Activator Proinflammatory cytokine 03 medical and health sciences chemistry.chemical_compound Immune system Translational Sciences Plasminogen Activator Inhibitor 1 Matrix Metalloproteinase 14 medicine Humans Lung arteriosclerosis Chemistry Macrophages serpins matrix metalloproteinases Arteriosclerosis medicine.disease Fibrosis Urokinase-Type Plasminogen Activator Cell biology 030104 developmental biology Plasminogen activator inhibitor-1 Proteolysis Immunology ComputingMethodologies_DOCUMENTANDTEXTPROCESSING Cardiology and Cardiovascular Medicine |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.117.309383 |
| Popis: | Supplemental Digital Content is available in the text. Objective— Macrophages are versatile immune cells capable of polarizing into functional subsets depending on environmental stimulation. In atherosclerotic lesions, proinflammatory polarized macrophages are associated with symptomatic plaques, whereas Th2 (T-helper cell type 2) cytokine–polarized macrophages are inversely related with disease progression. To establish a functional cause for these observations, we analyzed extracellular matrix degradation phenotypes in polarized macrophages. Approach and Results— We provide evidence that proinflammatory polarized macrophages rely on membrane-bound proteases including MMP-14 (matrix metalloproteinase-14) and the serine protease uPA (urokinase plasminogen activator) together with its receptor uPAR for extracellular matrix degradation. In contrast, Th2 cytokine alternatively primed macrophages do not show different proteolytic activity in comparison to unpolarized macrophages and lack increased localization of MMP-14 and uPA receptor to the cell membrane. Nonetheless, they express the highest amount of the serine protease uPA. However, uPA activity is blocked by similarly increased expression of its inhibitor PAI-1 (plasminogen activator inhibitor 1). When inhibiting PAI-1 or when analyzing macrophages deficient in PAI-1, Th2 cytokine–polarized macrophages display the same matrix degradation capability as proinflammatory-primed macrophages. Within atherosclerotic lesions, macrophages positive for the alternative activation marker CD206 express high levels of PAI-1. In addition, to test changed tissue remodeling capacities of alternatively activated macrophages, we used a bleomycin lung injury model in mice reconstituted with PAI-1−/− bone marrow. These results supported an enhanced remodeling phenotype displayed by increased fibrosis and elevated MMP activity in the lung after PAI-1 loss. Conclusions— We were able to demonstrate matrix degradation dependent on membrane-bound proteases in proinflammatory stimulated macrophages and a forced proteolytical quiescence in alternatively polarized macrophages by the expression of PAI-1. |
| Databáze: | OpenAIRE |
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