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

Abstract

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.

Keywords:

• Adenosine A2a receptor
• neutrophilic inflammation
• SARS-CoV-2
• Th17 cells

Disclosure statement

Sho Matsushita is an employee of iMmno, Inc. The other authors declare no conflicts of interest in association with the present study.

Additional information

Funding

This work was supported by a Grant-in-Aid for Young Scientists (no. 22K15735) to M.T., a Grant-in-Aid for Scientific Research (C) (no. 22K06731), awarded to M.K., a Grant-in-Aid for Young Scientists (no. 21K09920) to R.T., and a Grant-in-Aid for Scientific Research (C) (no. 22K08549) awarded to S.M. by the Japanese Society for the Promotion of Science. This work was also supported by the 44th and 45th Science Research Promotion Fund, awarded to M.K. by the Promotion and Mutual Aid Corporation for Private Schools of Japan.