Neutrophil accumulation and NET release contribute to thrombosis in HIT
Neutrophil accumulation and NET release contribute to thrombosis in HIT
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DOI：
10.1172/jci.insight.99445
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发表时间：
2018-09-20
期刊：
影响因子：
8
通讯作者：
Poncz, Mortimer
中科院分区：
文献类型：
--
作者：
Gollomp, Kandace;Kim, Minna;Poncz, Mortimer
肝素诱导的血小板减少症（HIT）是一种与严重血栓前状态相关的免疫介导的血小板减少性疾病。我们研究了中性粒细胞和中性粒细胞胞外陷阱（NET）是否有助于HIT血栓形成的发展。使用内皮化的微流控系统和小鼠被动免疫模型，我们表明，HIT诱导导致增加中性粒细胞粘附静脉内皮。在HIT小鼠中，新生静脉血栓下游的内皮粘附立即增强，之后中性粒细胞通过CXCR 2依赖性机制逆行迁移，积聚到血栓中。使用微流控系统，我们发现PF 4与NET结合，使它们变得紧凑并具有DNase抗性。PF 4-NET复合物选择性地结合HIT抗体，这进一步保护它们免受核酸酶消化。在HIT小鼠中，通过Padi 4基因破坏或DNA酶处理抑制NET形成限制了静脉血栓大小。PAD 4失活确实影响HIT患者的动脉血栓或血小板减少症的严重程度。因此，嗜中性粒细胞活化通过增强嗜中性粒细胞-内皮粘附和嗜中性粒细胞凝块浸润促进HIT中静脉血栓形成的发展，其中并入的PF 4-NET-HIT抗体复合物导致血栓形成传播。应探讨抑制中性粒细胞内皮粘附、预防中性粒细胞趋化因子依赖性的中性粒细胞向血栓的募集或抑制NET释放作为预防HIT患者静脉血栓形成的策略。
Heparin-induced thrombocytopenia (HIT) is an immune-mediated thrombocytopenic disorder associated with a severe prothrombotic state. We investigated whether neutrophils and neutrophil extracellular traps (NETs) contribute to the development of thrombosis in HIT. Using an endothelialized microfluidic system and a murine passive immunization model, we show that HIT induction leads to increased neutrophil adherence to venous endothelium. In HIT mice, endothelial adherence is enhanced immediately downstream of nascent venous thrombi, after which neutrophils undergo retrograde migration via a CXCR2-dependent mechanism to accumulate into the thrombi. Using a microfluidic system, we found that PF4 binds to NETs, leading them to become compact and DNase resistant. PF4-NET complexes selectively bind HIT antibodies, which further protect them from nuclease digestion. In HIT mice, inhibition of NET formation through Padi4 gene disruption or DNase treatment limited venous thrombus size. PAD4 inactivation did affect arterial thrombi or severity of thrombocytopenia in HIT. Thus, neutrophil activation contributes to the development of venous thrombosis in HIT by enhancing neutrophil-endothelial adhesion and neutrophil clot infiltration, where incorporated PF4-NET-HIT antibody complexes lead to thrombosis propagation. Inhibition of neutrophil endothelial adhesion, prevention of neutrophil chemokine-dependent recruitment of neutrophils to thrombi, or suppression of NET release should be explored as strategies to prevent venous thrombosis in HIT.