CCL5 derived from platelets increases megakaryocyte proplatelet formation
CCL5 derived from platelets increases megakaryocyte proplatelet formation
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DOI：
10.1182/blood-2015-05-644583
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发表时间：
2016-02-18
期刊：
影响因子：
20.3
通讯作者：
Battinelli, Elisabeth M.
中科院分区：
文献类型：
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作者：
Machlus, Kellie R.;Johnson, Kelly E.;Battinelli, Elisabeth M.
在生理压力的时候，血小板计数可以短暂上升。是什么引发了这种反应性血小板增多症是知之甚少。有趣的是，我们发现用活化血小板的释放物处理巨核细胞（MK）可使前血小板生成增加47%。血小板储存炎性细胞因子，包括趋化因子配体5（CCL 5，RANTES）; TRAP激活后，血小板释放超过25 ng/mL的CCL 5。我们假设CCL 5可以通过与MK上的受体CCR 5结合来调节血小板的产生。Maraviroc（CCR 5拮抗剂）或CCL 5免疫耗竭分别减少了95%和70%的血小板释放作用，表明源自血小板的CCL 5足以通过MK CCR 5驱动血小板生成增加。用重组CCL 5培养的MK使前血小板产生增加50%，并具有显著更高的倍性。在暴露于CCL 5之前用马拉韦罗预处理MK培养物逆转了增加的前血小板形成和倍性，表明CCL 5以CCR 5依赖性方式增加MK倍性和前血小板形成。对Akt信号通路的研究表明，CCL 5/CCR 5可能通过抑制细胞凋亡来影响前血小板的产生。在体内小鼠急性结肠炎模型中，血小板计数与炎症显著相关，而马拉韦罗治疗消除了这种相关性。我们认为，通过CCR 5的CCL 5信号可能会增加血小板计数在生理应激。
In times of physiological stress, platelet count can transiently rise. What initiates this reactive thrombocytosis is poorly understood. Intriguingly, we found that treating megakaryocytes (MKs) with the releasate from activated platelets increased proplatelet production by 47%. Platelets store inflammatory cytokines, including the chemokine ligand 5 (CCL5, RANTES); after TRAP activation, platelets release over 25 ng/mL CCL5. We hypothesized that CCL5 could regulate platelet production by binding to its receptor, CCR5, on MKs. Maraviroc (CCR5 antagonist) or CCL5 immunodepletion diminished 95% and 70% of the effect of platelet releasate, respectively, suggesting CCL5 derived from platelets is sufficient to drive increased platelet production through MK CCR5. MKs cultured with recombinant CCL5 increased proplatelet production by 50% and had significantly higher ploidy. Pretreating the MK cultures with maraviroc prior to exposure to CCL5 reversed the augmented proplatelet formation and ploidy, suggesting that CCL5 increases MK ploidy and proplatelet formation in a CCR5-dependent manner. Interrogation of the Akt signaling pathway suggested that CCL5/CCR5 may influence proplatelet production by suppressing apoptosis. In an in vivo murine acute colitis model, platelet count significantly correlated with inflammation whereas maraviroc treatment abolished this correlation. We propose that CCL5 signaling through CCR5 may increase platelet counts during physiological stress.