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.

Bioinformatics Department of the Research Institute of Molecular Pathology and the Institute of Molecular Biotechnology of the Austrian Academy of Sciences Vienna Austria

Center for Biomedical Technology Danube University Krems Krems Austria

Centre National de la Recherche Scientifique UMR 8104 Paris France

Centre of Biological Engineering University of Minho Campus of Gualtar Braga Portugal

Clinical Department of Medical and Chemical Laboratory Diagnostics Medical University of Vienna Vienna Austria

Department of Transfusion Medicine Medical University of Vienna Vienna Austria

Division of Rheumatology Internal Medicine 3 Medical University of Vienna Vienna Austria

EXBIO Praha Vestec Czechia

Institut National de la Santé et de la Recherche Médicale INSERM U1016 Institut Cochin Paris France

Institute of Immunology Center for Pathophysiology Infectiology and Immunology Medical University of Vienna Vienna Austria

Laboratory of Molecular Immunology Institute of Molecular Biology Slovak Academy of Sciences Bratislava Slovakia

Molecular Immunology Unit Institute for Hygiene and Applied Immunology Center for Pathophysiology Infectiology and Immunology Medical University of Vienna Vienna Austria

The Center for Advanced Biomedical Sciences and Swine Research Kagoshima University Kagoshima Japan

Université Paris Descartes Paris France

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