Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome

Potentiation of neutrophil extracellular trap(NET) release is one mechanism by which antiphospholipid antibodies (aPL Abs) effect thrombotic events in patients with antiphospholipid syndrome(APS). Surface adenosine receptorstrigger cyclic AMP (cAMP) formation in neutrophils, and this mechanism has been proposed to regulate NETosis in some contexts. Here we report that selective agonismof the adenosine A2A receptor(CGS21680) suppresses aPL Ab-mediated NETosis in protein kinase A-dependent fashion. CGS21680 also reduces thrombosis in the inferior vena cavaeof both control mice and mice administered aPL Abs. The antithromboticmedication dipyridamoleis known to potentiate adenosinesignaling by increasing extracellular concentrations of adenosineand interfering with the breakdown of cAMP. Like CGS21680, dipyridamolesuppresses aPL Ab-mediated NETosis via the adenosine A2A receptorand mitigates venous thrombosis in mice. In summary, these data suggest an anti-inflammatory therapeutic paradigm in APS, which may extend to thrombotic disease in the general population.