Extracellular Purine Metabolism Is the Switchboard of Immunosuppressive Macrophages and a Novel Target to Treat Diseases With Macrophage Imbalances

If misregulated, macrophage (M phi)-T cell interactions can drive chronic inflammation thereby causing diseases, such as rheumatoid arthritis (RA). We report that in a proinflammatory environment, granulocyte-M phi (GM-CSF)- and M phi colony-stimulating factor (M-CSF)-dependent Mcps have dichotomous effects on T cell activity. While GM-CSF-dependent Mcps show a highly stimulatory activity typical for M1 M phi s, M-CSF-dependent M phi s, marked by folate receptor beta (FR beta), 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 Mks 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 beta(+)CD39(+)CD73(+) M phi(j)s, which boosts adenosine production and curtails the dominance of proinflammatory M phi s. In contrast to untargeted MTX, this approach leads to potent alleviation of inflammation in the murine arthritis model. In conclusion, we define the M phi extracellular purine metabolism as a novel checkpoint in M phi cell fate decision-making and an attractive target to control pathological Mcps in immune-mediated diseases.