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

Abstract

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. 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 rheumatoid arthritis. 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 Rheumatoid Arthritis, 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 will also be discussed.

A defect in KCa3.1 channel activity limits the ability of CD8 + T cells from cancer patients to infiltrate an adenosine-rich microenvironment

“…We observed a comparable effect of adenosine and the A 2A R agonist CGS21680 on the chemotaxis of HNSCC CD8 + T cells, suggesting that differences in the adenosine signaling pathway and not adenosine degradation are responsible for the heightened effect of adenosine on chemotaxis. It is well established that A 2A R mediates the effect of adenosine in human T cells (5, 17, 51–53). We have previously shown that adenosine inhibits the motility of human CD3 + T cells and cytokine release through A 2A R stimulation, activation of adenylyl cyclase and PKAI, and ultimately inhibition of KCa3.1 channels (22).…”

Perturbation of the human gut microbiome by a non-antibiotic drug contributes to the resolution of autoimmune disease

“…Although MTX has been used for several decades to reduce inflammation in patients with autoimmune disease, the mechanisms by which it does so are not fully understood. A leading hypothesis is that MTX directly inhibits an enzyme called AICAR transformylase, resulting in an increase in extracellular levels of adenosine, a potent anti-inflammatory mediator 14,45 . Other possible mechanisms that have been investigated suggest that MTX may affect cytokine production by immune cells, such as by decreasing the production of the proinflammatory cytokine TNFα 46 or increasing the production of the α-inflammatory cytokine IL-10 47 .…”

The Effect of Adenosine on Extracellular Matrix Production in Porcine Intervertebral Disc Cells

“…Elevation of proinflammatory mediators in degenerated discs upregulates the expression of matrix-degrading enzymes [Risbud and Shapiro, 2014]. Since adenosine is also known as a potent endogenous inhibitor of inflammatory processes in the human body [Fredholm et al, 1994;Linden, 2005;Hasko et al, 2008;Hasko and Cronstein, 2013;Cronstein and Sitkovsky, 2017], adenosine can be a potential therapeutic agent for disc degeneration. …”

“…Anti-inflammatory activities of adenosine are primarily medicated through the adenosine A2A receptor [Tesch et al, 2004;Cronstein and Sitkovsky, 2017]. In addition, activation of AMPK has also been shown to exhibit anti-inflammatory effects [Mancini et al, 2017].…”

“…Adenosine has been proposed as a local modulator of inflammation via receptor activation [Fredholm et al, 1994;Linden, 2005;Hasko et al, 2008;Hasko and Cronstein, 2013;Cronstein and Sitkovsky, 2017]. Anti-inflammatory activities of adenosine are primarily medicated through the adenosine A2A receptor [Tesch et al, 2004;Cronstein and Sitkovsky, 2017].…”