Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice
Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice
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DOI：
10.1182/blood-2016-04-710632
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发表时间：
2016-11-17
期刊：
影响因子：
20.3
通讯作者：
Massberg, Steffen
中科院分区：
文献类型：
--
作者：
Stark, Konstantin;Philippi, Vanessa;Massberg, Steffen
深静脉血栓形成（DVT）是最常见的心血管疾病之一，但其病理生理机制尚不完全清楚。尽管无菌炎症最近被证明可以促进DVT期间的凝血，但其潜在的分子机制尚未完全解决，这可能潜在地确定新的抗炎方法来预防和治疗DVT。利用下腔静脉血流减少引起的小鼠静脉血栓形成模型，我们发现血源性高迁移率组盒1蛋白（HMGB1）是无菌炎症的典型介质，是血小板和髓系白细胞促进闭塞性DVT形成的血栓前级联反应的主要调节剂。将血小板转移到Hmgb1（-/-）嵌合体中表明，这种细胞类型是Hmgb1的主要来源，在激活时暴露在其表面上减少的Hmgb1，从而增强单核细胞的募集。活化的白细胞反过来支持HMGB1的氧化，释放其血栓前活性并促进血小板聚集。这增强了HMGB1的数量，并通过晚期糖基化终产物受体（RAGE）和toll样受体2进一步培养单核细胞的积累和激活，导致单核细胞来源的组织因子和细胞因子的局部递送。此外，二硫化物HMGB1促进RAGE介导的血栓形成性中性粒细胞胞外陷阱（NETs）的形成，使其胞外DNA链上暴露出额外的HMGB1。最终，凝血和炎症的恶性循环导致梗阻性深静脉血栓形成。因此，血小板来源的二硫化物HMGB1是静脉血栓形成无菌炎症过程的中心介质，可能是预防深静脉血栓形成的抗炎方法的一个有吸引力的靶点。
Deep venous thrombosis (DVT) is one of the most common cardiovascular diseases, but its pathophysiology remains incompletely understood. Although sterile inflammation has recently been shown to boost coagulation during DVT, the underlying molecular mechanisms are not fully resolved, which could potentially identify new anti-inflammatory approaches to prophylaxis and therapy of DVT. Using a mouse model of venous thrombosis induced by flow reduction in the vena cava inferior, we identified blood-derived high-mobility group box 1 protein (HMGB1), a prototypical mediator of sterile inflammation, to be a master regulator of the prothrombotic cascade involving platelets and myeloid leukocytes fostering occlusive DVT formation. Transfer of platelets into Hmgb1(-/-) chimeras showed that this cell type is the major source of HMGB1, exposing reduced HMGB1 on their surface upon activation thereby enhancing the recruitment of monocytes. Activated leukocytes in turn support oxidation of HMGB1 unleashing its prothrombotic activity and promoting platelet aggregation. This potentiates the amount of HMGB1 and further nurtures the accumulation and activation of monocytes through receptor for advanced glycation end products (RAGE) and Toll-like receptor 2, leading to local delivery of monocyte-derived tissue factor and cytokines. Moreover, disulfide HMGB1 facilitates formation of prothrombotic neutrophil extracellular traps (NETs) mediated by RAGE, exposing additional HMGB1 on their extracellular DNA strands. Eventually, a vicious circle of coagulation and inflammation is set in motion leading to obstructive DVT formation. Therefore, platelet-derived disulfide HMGB1 is a central mediator of the sterile inflammatory process in venous thrombosis and could be an attractive target for an anti-inflammatory approach for DVT prophylaxis.