Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases

Key Points Adenosine, generated from the extracellular hydrolysis of ATP, is a potent endogenous regulator of inflammation and immune reactions via interaction with one or more cell surface receptors The principal adenosine receptor involved in regulation of adaptive T cell responses is A 2a A 2a , A 2b and A 3 downregulate macrophage-mediated inflammatory actions, although A 2b might indirectly stimulate type 17 T helper cell immune responses via increased IL-6 production Adenosine mediates the anti-inflammatory effects of low-dose methotrexate treatment as well as some of the anti-inflammatory effects of sulfasalazine Cronstein and Sitkovsky discuss the metabolic changes that regulate adenosine levels in inflamed tissue, the receptors that mediate the effects of adenosine and their role in rheumatic diseases, as well as the potential role for therapeutic targeting of adenosine and its receptors. Adenosine, a nucleoside derived primarily from the extracellular hydrolysis of adenine nucleotides, is a potent regulator of inflammation. Adenosine mediates its effects on inflammatory cells by engaging one or more cell-surface receptors. The expression and function of adenosine receptors on different cell types change during the course of rheumatic diseases, such as rheumatoid arthritis (RA). Targeting adenosine receptors directly for the treatment of rheumatic diseases is currently under study; however, indirect targeting of adenosine receptors by enhancing adenosine levels at inflamed sites accounts for most of the anti-inflammatory effects of methotrexate, the anchor drug for the treatment of RA. In this Review, we discuss the regulation of extracellular adenosine levels and the role of adenosine in regulating the inflammatory and immune responses in rheumatic diseases such as RA, psoriasis and other types of inflammatory arthritis. In addition, adenosine and its receptors are involved in promoting fibrous matrix production in the skin and other organs, and the role of adenosine in fibrosis and fibrosing diseases is also discussed.