Frontiers in Immunology (Apr 2018)
Extracellular Purine Metabolism Is the Switchboard of Immunosuppressive Macrophages and a Novel Target to Treat Diseases With Macrophage Imbalances
- Anna Ohradanova-Repic,
- Christian Machacek,
- Celine Charvet,
- Celine Charvet,
- Celine Charvet,
- Franck Lager,
- Franck Lager,
- Franck Lager,
- Delphine Le Roux,
- Delphine Le Roux,
- Delphine Le Roux,
- René Platzer,
- Vladimir Leksa,
- Vladimir Leksa,
- Goran Mitulovic,
- Thomas R. Burkard,
- Gerhard J. Zlabinger,
- Michael B. Fischer,
- Michael B. Fischer,
- Vincent Feuillet,
- Vincent Feuillet,
- Vincent Feuillet,
- Gilles Renault,
- Gilles Renault,
- Gilles Renault,
- Stephan Blüml,
- Miroslav Benko,
- Miloslav Suchanek,
- Johannes B. Huppa,
- Takami Matsuyama,
- Artur Cavaco-Paulo,
- Georges Bismuth,
- Georges Bismuth,
- Georges Bismuth,
- Hannes Stockinger
Affiliations
- Anna Ohradanova-Repic
- Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
- Christian Machacek
- Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
- Celine Charvet
- Institut National de la Santé et de la Recherche Médicale, INSERM U1016, Institut Cochin, Paris, France
- Celine Charvet
- Université Paris Descartes, Paris, France
- Celine Charvet
- Centre National de la Recherche Scientifique (CNRS), UMR 8104, Paris, France
- Franck Lager
- Institut National de la Santé et de la Recherche Médicale, INSERM U1016, Institut Cochin, Paris, France
- Franck Lager
- Université Paris Descartes, Paris, France
- Franck Lager
- Centre National de la Recherche Scientifique (CNRS), UMR 8104, Paris, France
- Delphine Le Roux
- Institut National de la Santé et de la Recherche Médicale, INSERM U1016, Institut Cochin, Paris, France
- Delphine Le Roux
- Université Paris Descartes, Paris, France
- Delphine Le Roux
- Centre National de la Recherche Scientifique (CNRS), UMR 8104, Paris, France
- René Platzer
- Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
- Vladimir Leksa
- Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
- Vladimir Leksa
- Laboratory of Molecular Immunology, Institute of Molecular Biology, Slovak Academy of Sciences, Bratislava, Slovakia
- Goran Mitulovic
- Clinical Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
- Thomas R. Burkard
- Bioinformatics Department of the Research Institute of Molecular Pathology and the Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
- Gerhard J. Zlabinger
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
- Michael B. Fischer
- Department of Transfusion Medicine, Medical University of Vienna, Vienna, Austria
- Michael B. Fischer
- 0Center for Biomedical Technology, Danube University Krems, Krems, Austria
- Vincent Feuillet
- Institut National de la Santé et de la Recherche Médicale, INSERM U1016, Institut Cochin, Paris, France
- Vincent Feuillet
- Université Paris Descartes, Paris, France
- Vincent Feuillet
- Centre National de la Recherche Scientifique (CNRS), UMR 8104, Paris, France
- Gilles Renault
- Institut National de la Santé et de la Recherche Médicale, INSERM U1016, Institut Cochin, Paris, France
- Gilles Renault
- Université Paris Descartes, Paris, France
- Gilles Renault
- Centre National de la Recherche Scientifique (CNRS), UMR 8104, Paris, France
- Stephan Blüml
- 1Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Miroslav Benko
- 2EXBIO Praha, Vestec, Czechia
- Miloslav Suchanek
- 2EXBIO Praha, Vestec, Czechia
- Johannes B. Huppa
- Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
- Takami Matsuyama
- 3The Center for Advanced Biomedical Sciences and Swine Research, Kagoshima University, Kagoshima, Japan
- Artur Cavaco-Paulo
- 4Centre of Biological Engineering, University of Minho, Campus of Gualtar, Braga, Portugal
- Georges Bismuth
- Institut National de la Santé et de la Recherche Médicale, INSERM U1016, Institut Cochin, Paris, France
- Georges Bismuth
- Université Paris Descartes, Paris, France
- Georges Bismuth
- Centre National de la Recherche Scientifique (CNRS), UMR 8104, Paris, France
- Hannes Stockinger
- Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
- DOI
- https://doi.org/10.3389/fimmu.2018.00852
- Journal volume & issue
-
Vol. 9
Abstract
If misregulated, macrophage (Mϕ)–T cell interactions can drive chronic inflammation thereby causing diseases, such as rheumatoid arthritis (RA). We report that in a proinflammatory environment, granulocyte-Mϕ (GM-CSF)- and Mϕ colony-stimulating factor (M-CSF)-dependent Mϕs have dichotomous effects on T cell activity. While GM-CSF-dependent Mϕs show a highly stimulatory activity typical for M1 Mϕs, M-CSF-dependent Mϕs, marked by folate receptor β (FRβ), adopt an immunosuppressive M2 phenotype. We find the latter to be caused by the purinergic pathway that directs release of extracellular ATP and its conversion to immunosuppressive adenosine by co-expressed CD39 and CD73. Since we observed a misbalance between immunosuppressive and immunostimulatory Mϕs in human and murine arthritic joints, we devised a new strategy for RA treatment based on targeted delivery of a novel methotrexate (MTX) formulation to the immunosuppressive FRβ+CD39+CD73+ Mϕs, which boosts adenosine production and curtails the dominance of proinflammatory Mϕs. In contrast to untargeted MTX, this approach leads to potent alleviation of inflammation in the murine arthritis model. In conclusion, we define the Mϕ extracellular purine metabolism as a novel checkpoint in Mϕ cell fate decision-making and an attractive target to control pathological Mϕs in immune-mediated diseases.
Keywords
- macrophage polarization
- chronic inflammation
- macrophage-T cell interaction
- purine metabolism
- adenosine
- methotrexate