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.

• Klíčová slova
• adenosine, chronic inflammation, macrophage polarization, macrophage-T cell interaction, methotrexate, purine metabolism, rheumatoid arthritis,
• MeSH
• adenosin imunologie   MeSH
• buněčná diferenciace * MeSH
• faktor stimulující granulocyto-makrofágové kolonie farmakologie   MeSH
• faktor stimulující kolonie makrofágů farmakologie   MeSH
• imunosupresiva aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• makrofágy imunologie   metabolismus   MeSH
• methotrexát aplikace a dávkování   terapeutické užití   MeSH
• modely nemocí na zvířatech MeSH
• monocyty účinky léků   MeSH
• myši MeSH
• proliferace buněk MeSH
• puriny metabolismus   MeSH
• revmatoidní artritida farmakoterapie   imunologie   MeSH
• synoviální tekutina cytologie   imunologie   MeSH
• zánět farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosin MeSH
• faktor stimulující granulocyto-makrofágové kolonie MeSH
• faktor stimulující kolonie makrofágů MeSH
• imunosupresiva MeSH
• methotrexát MeSH
• puriny MeSH