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TitleExtracellular purine metabolism is the switchboard of immunosuppressive macrophages and a novel target to treat diseases with macrophage imbalances
Author(s)Ohradanova-Repic, Anna
Machacek, Christian
Charvet, Celine
Lager, Franck
Le Roux, Delphine
Platzer, René
Leksa, Vladimir
Mitulovic, Goran
Burkard, Thomas R.
Zlabinger, Gerhard J.
Fischer, Michael B.
Feuillet, Vincent
Renault, Gilles
Blüml, Stephan
Benko, Miroslav
Suchanek, Miloslav
Huppa, Johannes B.
Matsuyama, Takami
Cavaco-Paulo, Artur
Bismuth, Georges
Stockinger, Hannes
Keywordsmacrophage polarization
chronic inflammation
macrophage-T cell interaction
purine metabolism
rheumatoid arthritis
Issue date2018
PublisherFrontiers Media
JournalFrontiers in Immunology
CitationOhradanova-Repic, Anna; Machacek, Christian; Charvet, Celine; Lager, Franck; Le Roux, Delphine; Platzer, René; Leksa, Vladimir; Mitulovic, Goran; Burkard, Thomas R.; Zlabinger, Gerhard J.; Fischer, Michael B.; Feuillet, Vincent; Renault, Gilles; Blüml, Stephan; Benko, Miroslav; Suchanek, Miloslav; Huppa, Johannes B.; Matsuyama, Takami; Cavaco-Paulo, Artur; Bismuth, Georges; Stockinger, Hannes, Extracellular Purine Metabolism Is the Switchboard of Immunosuppressive Macrophages and a Novel Target to Treat Diseases With Macrophage Imbalances. Frontiers in Immunology, 9(852), 2018
Abstract(s)If misregulated, macrophage (M)T cell interactions can drive chronic inflammation thereby causing diseases, such as rheumatoid arthritis (RA). We report that in a proinflammatory environment, granulocyte-M (GM-CSF)- and M colony-stimulating factor (M-CSF)-dependent Ms have dichotomous effects on T cell activity. While GM-CSF-dependent Ms show a highly stimulatory activity typical for M1 Ms, M-CSF-dependent Ms, marked by folate receptor (FR), 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 Ms 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 FR+CD39+CD73+ Ms, which boosts adenosine production and curtails the dominance of proinflammatory Ms. In contrast to untargeted MTX, this approach leads to potent alleviation of inflammation in the murine arthritis model. In conclusion, we define the M extracellular purine metabolism as a novel checkpoint in M cell fate decision-making and an attractive target to control pathological Ms in immune-mediated diseases.
AccessOpen access
Appears in Collections:CEB - Publicações em Revistas/Séries Internacionais / Publications in International Journals/Series

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