Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome

Ramadan A. Ali, Alex A. Gandhi, He Meng, Srilakshmi Yalavarthi, Andrew P. Vreede, Shanea K. Estes, Olivia R. Palmer, Paula L. Bockenstedt, David J. Pinsky, Joan M. Greve, Jose A. Diaz, Yogendra Kanthi and Jason S. Knight ()
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Ramadan A. Ali: University of Michigan
Alex A. Gandhi: University of Michigan
He Meng: University of Michigan
Srilakshmi Yalavarthi: University of Michigan
Andrew P. Vreede: University of Michigan
Shanea K. Estes: University of Michigan
Olivia R. Palmer: University of Michigan
Paula L. Bockenstedt: University of Michigan Medical School
David J. Pinsky: University of Michigan
Joan M. Greve: University of Michigan
Jose A. Diaz: University of Michigan
Yogendra Kanthi: University of Michigan
Jason S. Knight: University of Michigan

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09801-x

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