Extracellular adenosine induces hypersecretion of IL-17A by T-helper 17 cells through the adenosine A2a receptor to promote neutrophilic inflammation

Abstract

Extracellular adenosine, produced from ATP secreted by neuronal or immune cells, may play a role in endogenous regulation of inflammatory responses. However, the underlying molecular mechanisms are largely unknown. Here, we show that adenosine primes hypersecretion of interleukin (IL)-17A by CD4+ T cells via T cell receptor activation. This hypersecretion was also induced by an adenosine A2a receptor (A2aR) agonist, PSB0777. In addition, an A2aR antagonist, Istradefylline, and inhibitors of adenylcyclase and protein kinase A (both of which are signaling molecules downstream of the Gs protein coupled with the A2aR), suppressed IL-17A production, suggesting that activation of A2aR induces IL-17A production by CD4+ T cells. Furthermore, immune subset studies revealed that adenosine induced hypersecretion of IL-17A by T-helper (Th)17 cells. These results indicate that adenosine is an endogenous modulator of neutrophilic inflammation. Administration of an A2aR antagonist to mice with experimental autoimmune encephalomyelitis led to marked amelioration of symptoms, suggesting that suppression of adenosine-mediated IL-17A production is an effective treatment for Th17-related autoimmune diseases.

Istradefylline, an adenosine A2a receptor antagonist, ameliorates neutrophilic airway inflammation and psoriasis in mice

“…Furthermore, we reported that adenosine is produced by activated CD4 + T cells, and primes hypersecretion of IL-17A by CD4 + T cells through A2aR. 38 These results suggest that CD39 and CD73 expressed on the CD4 + T cell surface converts ATP to adenosine, and adenosine binds to A2aR and primes hypersecretion of IL-17A (Figure 5). Some researchers argue that an A2aR agonist, CGS21680, suppresses Th17 differentiation.…”

“…Similarly, ARL67156 and AMP-CP, which inhibit the production of adenosine, suppressed IL-17-dependent neutrophilic airway inflammation, which corroborates our previous findings. 38 [51][52][53][54] In recent previous studies, patients with severe COVID-19 showed the aberrant activation of neutrophils and Th17 promotion, 55 and IL-17 can serve as a biomarker of the severity of COVID-19. 56 Indeed, autopsy samples from the lungs of COVID-19 patients showed neutrophil infiltration in pulmonary capillaries, 57 and the peripheral blood of patients showed an increased frequency of Th17 cells.…”

“…[64][65][66] Because CGS21680 is much less selective than the A2aR agonist we used in a recent previous study (PSB0777), it is highly conceivable that these studies gave contradictory results. 38 In addition, some researchers argue that methotrexate exerts an anti-rheumatic effect by promoting adenosine release. 6 Indeed, different expression patterns of dopamine receptor subtypes are observed on different populations of immune cells, depending on the activation status of cells.…”

“…Istradefylline, an inhibitor of CD39 (ARL67156) and an inhibitor of CD73 (AMP-CP) suppressed IL-17A production, and the administration of istradefylline to mice with experimental autoimmune encephalomyelitis led to the marked amelioration of symptoms. 38 These results suggest that adenosine is an endogenous modulator of neutrophilic inflammation.…”