Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome
Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome
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DOI：
10.1038/s41467-019-09801-x
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发表时间：
2019-04-23
影响因子：
16.6
通讯作者：
Knight, Jason S.
中科院分区：
文献类型：
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作者：
Ali, Ramadan A.;Gandhi, Alex A.;Knight, Jason S.
抗磷脂抗体(APL Abs)影响抗磷脂综合征(APS)患者血栓形成事件的机制之一是促进中性粒细胞胞外TRAP(Net)释放。表面腺苷受体可在中性粒细胞中触发环磷酸腺苷(CAMP)的形成，这一机制已被提出在某些情况下用于调节网织红细胞增多。在此，我们报道了腺苷A(2A)受体(CGS21680)的选择性激动剂以蛋白激酶A依赖的方式抑制APL-Ab介导的NETase。CGS21680还可以减少对照组和注射APL单抗的小鼠的下腔静脉血栓形成。众所周知，抗血栓药物双嘧达莫通过增加细胞外腺苷浓度和干扰cAMP的分解来增强腺苷信号。与CGS21680一样，双嘧达莫通过腺苷A(2A)受体抑制APL Ab介导的NETsis，并减轻小鼠静脉血栓形成。综上所述，这些数据提示了APS的抗炎治疗范例，这可能会延伸到普通人群中的血栓性疾病。
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.