G-CSF-mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands
G-CSF-mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands
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DOI：
10.1182/blood-2010-09-308387
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发表时间：
2011-04-21
期刊：
影响因子：
20.3
通讯作者：
Gunzer, Matthias
中科院分区：
文献类型：
--
作者：
Koehler, Anja;De Filippo, Katia;Gunzer, Matthias
从骨髓(BM)紧急动员中性粒细胞是早期细胞免疫的关键事件。造血细胞因子粒细胞集落刺激因子(G-CSF)刺激了这一过程，但单个中性粒细胞如何原位反应尚不清楚。我们通过活体双光子显微镜显示，全身注射临床级G-CSF可迅速诱导中性粒细胞移动并进入小鼠胫骨BM内的血管。同时，中性粒细胞趋化因子KC(CXCL1)在血液中激增。在缺乏KC受体CXCR2的小鼠中，G-CSF不能动员中性粒细胞，抗体阻断CXCR2抑制了中性粒细胞在骨髓中的动员和诱导。KC由巨核细胞和内皮细胞原位表达，并由直接从骨髓中分离的巨核细胞在体外释放。这种KC的产生被血小板生成素(TPO)强烈地促进。全身性G-CSF可迅速诱导骨髓细胞产生TPO。因此，一次注射TPO动员中性粒细胞的动力学类似于G-CSF，而缺乏TPO受体的小鼠在短期注射G-CSF后表现出中性粒细胞动员的损害。因此，一个由信号分子、趋化因子和细胞组成的网络控制着中性粒细胞从骨髓中的释放，它们的动员涉及到由TPO作为起搏器控制的快速诱导的CXCR2介导的运动。(血。2011；117(16)：4349-4357)
Emergency mobilization of neutrophil granulocytes (neutrophils) from the bone marrow (BM) is a key event of early cellular immunity. The hematopoietic cytokine granulocyte-colony stimulating factor (G-CSF) stimulates this process, but it is unknown how individual neutrophils respond in situ. We show by intravital 2-photon microscopy that a systemic dose of human clinical-grade G-CSF rapidly induces the motility and entry of neutrophils into blood vessels within the tibial BM of mice. Simultaneously, the neutrophil-attracting chemokine KC (Cxcl1) spikes in the blood. In mice lacking the KC receptor Cxcr2, G-CSF fails to mobilize neutrophils and antibody blockade of Cxcr2 inhibits the mobilization and induction of neutrophil motility in the BM. KC is expressed by megakaryocytes and endothelial cells in situ and is released in vitro by megakaryocytes isolated directly from BM. This production of KC is strongly increased by thrombopoietin (TPO). Systemic G-CSF rapidly induces the increased production of TPO in BM. Accordingly, a single injection of TPO mobilizes neutrophils with kinetics similar to G-CSF, and mice lacking the TPO receptor show impaired neutrophil mobilization after short-term G-CSF administration. Thus, a network of signaling molecules, chemokines, and cells controls neutrophil release from the BM, and their mobilization involves rapidly induced Cxcr2-mediated motility controlled by TPO as a pacemaker. (Blood. 2011; 117(16): 4349-4357)