Istradefylline, an adenosine A2a receptor antagonist, inhibits the CD4+ T-cell hypersecretion of IL-17A and IL-8 in humans.

Extracellular adenosine produced from ATP plays a role in energy processes, neurotransmission, and inflammatory responses. Istradefylline is a selective adenosine A2a receptor (A2aR) antagonist used for the treatment of Parkinson's disease. We previously showed using mouse models that adenosine primes hypersecretion of interleukin (IL)-17A via A2aR, which plays a role in neutrophilic inflammation models in mice. This finding suggests that adenosine is an endogenous modulator of neutrophilic inflammation. We, therefore, investigated the in vitro effect of istradefylline in humans. In the present study, using human peripheral blood mononuclear cells (PBMCs), we tested the effect of adenosine, adenosine receptor agonists and istradefylline on cytokine responses using mixed lymphocyte reaction (MLR), PBMCs, CD4+ T cells, and Candida albicans antigen (Ag)-stimulated PBMCs. We showed that adenosine and an A2aR agonist (PSB0777) promoted IL-17A and IL-8 production from human PBMCs, and istradefylline suppressed this response. In addition, istradefylline inhibited not only the IL-17A and IL-8 production induced by adenosine but also that from C. albicans Ag-stimulated PBMCs. These results indicate that adenosine-mediated IL-17A and IL-8 production plays a role in neutrophilic inflammation, against which istradefylline should be effective.

Targeting adenosinergic pathway and adenosine A2A receptor signaling for the treatment of COVID-19: A hypothesis.

The most serious health issue today is the rapid outbreak of Coronavirus Disease 2019 (COVID-19). More than 6,973,427 confirmed cases were diagnosed in nearly 213 countries and territories around the world and two international conveyances, causing globally over 400,000 deaths. Epidemiology, risk factors, and clinical characteristics of COVID-19 patients have been identified, but the factors influencing the immune system against COVID-19 have not been well established. Upon infection or cell damage, high amounts of adenosine triphosphate (ATP) are released from damaged cells, which serve as mediators of inflammation through purinergic cell surface receptor signaling. As a protective mechanism to prevent excessive damage to host tissue, adenosine counteracts ATP's effects by adenosine receptor stimulation to suppress the pro-inflammatory response. Adenosine is seen as a major obstacle to the efficacy of immune therapies, and the adenosinergic axis components are critical therapeutic targets for cancer and microbial infections. Pharmacologic inhibitors or antibodies specific to adenosinergic pathway components or adenosine receptors in microbial and tumor therapy have shown efficacy in pre-clinical studies and are entering the clinical arena. In this review, we provide a novel hypothesis explaining the potential for improving the efficiency of innate and adaptive immune systems by targeting adenosinergic pathway components and adenosine A2A receptor signaling for the treatment of COVID-19.