Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome

• Published in: Nature communications Vol. 10; no. 1; p. 1916
• Main Authors: Ali, Ramadan A., Gandhi, Alex A., Meng, He, Yalavarthi, Srilakshmi, Vreede, Andrew P., Estes, Shanea K., Palmer, Olivia R., Bockenstedt, Paula L., Pinsky, David J., Greve, Joan M., Diaz, Jose A., Kanthi, Yogendra, Knight, Jason S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-04-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 14/1; 14/63; 631/250/2504/223/1699; 631/250/38; 64/60; 692/699/1670/122/1928; 692/699/75/593/567; 96/95; Adenosine; Adenosine - analogs & derivatives; Adenosine - immunology; Adenosine - metabolism; Adenosine - pharmacology; Adenosine A2 Receptor Agonists - pharmacology; Animal models; Animals; Antibodies; Antibodies, Antiphospholipid - blood; Antiphospholipid antibodies; Antiphospholipid syndrome; Antiphospholipid Syndrome - drug therapy; Antiphospholipid Syndrome - genetics; Antiphospholipid Syndrome - immunology; Antiphospholipid Syndrome - pathology; Autoimmune diseases; Cyclic AMP; Cyclic AMP - immunology; Cyclic AMP - metabolism; Dipyridamole; Dipyridamole - pharmacology; Disease Models, Animal; Extracellular Traps - drug effects; Extracellular Traps - immunology; Extracellular Traps - metabolism; Fibrinolytic Agents - pharmacology; Gene Expression Regulation; Humanities and Social Sciences; Humans; Immunoglobulin G - blood; Inflammation; Kinases; Leukocytes (neutrophilic); Male; Mice; Mice, Inbred C57BL; multidisciplinary; Neutrophils; Neutrophils - drug effects; Neutrophils - immunology; Phenethylamines - pharmacology; Protein kinase A; Receptor, Adenosine A2A - genetics; Receptor, Adenosine A2A - immunology; Receptors; Science; Science (multidisciplinary); Signal Transduction; Thromboembolism; Thrombosis; Vena Cava, Inferior - drug effects; Vena Cava, Inferior - immunology; Vena Cava, Inferior - metabolism; Venous Thrombosis - drug therapy; Venous Thrombosis - genetics; Venous Thrombosis - immunology; Venous Thrombosis - pathology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09801-x

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 A
2A
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 A
2A
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.
Antiphospholipid syndrome is characterised by increased neutrophil extracellular trap formation (NETosis) and, consequently, increased thrombotic events. Here Ali et al. show that treatment with adenosine receptor agonists suppresses NETosis and venous thrombosis in mouse models of antiphospholipid syndrome.