Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome

Ramadan A Ali,Shanea K Estes,Jose A Diaz,Paula L Bockenstedt,Yogendra Kanthi,Alex A Gandhi,Jason S Knight,He Meng,Joan M Greve,David J Pinsky,Andrew P Vreede,Olivia R Palmer,Srilakshmi Yalavarthi

doi:10.1038/s41467-019-09801-x

Abstract

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 receptors trigger cyclic AMP (cAMP) formation in neutrophils, and this mechanism has been proposed to regulate NETosis in some contexts. Here we report that selective agonism of the adenosine A2A receptor (CGS21680) suppresses aPL Ab-mediated NETosis in protein kinase A-dependent fashion. CGS21680 also reduces thrombosis in the inferior vena cavae of both control mice and mice administered aPL Abs. The antithrombotic medication dipyridamole is known to potentiate adenosine signaling by increasing extracellular concentrations of adenosine and interfering with the breakdown of cAMP. Like CGS21680, dipyridamole suppresses aPL Ab-mediated NETosis via the adenosine A2A receptor and 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.

Highlights

Potentiation of neutrophil extracellular trap (NET) release is one mechanism by which antiphospholipid antibodies effect thrombotic events in patients with antiphospholipid syndrome (APS)
We have demonstrated that purified control neutrophils display β2GPI—a key APS autoantigen—on their surface, and can be triggered to release NETs in TLR4-dependent fashion by exposure to anti-β2GPI isolated from APS patients[11]
Using a human/mouse chimeric model, we have shown that NETs are required for APS-potentiated thrombosis[12]

Summary

Introduction

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). Suppression by CGS21680 was effective when NETosis was activated by anti-β2GPI IgG that had been affinitypurified from the serum of an APS patient (Fig. 2d, e). These data demonstrate that the adenosine A2A receptor agonist CGS21680 suppresses NETosis triggered by APS patient antibodies, and that PKA is a downstream effector of this suppression.

Results

Conclusion