Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
J Clin Invest. 2010 Jul;120(7):2423-31. doi: 10.1172/JCI41649.
Neutrophils are a major component of the innate immune response. Their homeostasis is maintained, in part, by the regulated release of neutrophils from the bone marrow. Constitutive expression of the chemokine CXCL12 by bone marrow stromal cells provides a key retention signal for neutrophils in the bone marrow through activation of its receptor, CXCR4. Attenuation of CXCR4 signaling leads to entry of neutrophils into the circulation through unknown mechanisms. We investigated the role of CXCR2-binding ELR+ chemokines in neutrophil trafficking using mouse mixed bone marrow chimeras reconstituted with Cxcr2(-/-) and WT cells. In this context, neutrophils lacking CXCR2 were preferentially retained in the bone marrow, a phenotype resembling the congenital disorder myelokathexis, which is characterized by chronic neutropenia. Additionally, transient disruption of CXCR4 failed to mobilize Cxcr2(-/-) neutrophils. However, neutrophils lacking both CXCR2 and CXCR4 displayed constitutive mobilization, showing that CXCR4 plays a dominant role in neutrophil trafficking. With regard to CXCR2 ligands, bone marrow endothelial cells and osteoblasts constitutively expressed the ELR+ chemokines CXCL1 and CXCL2, and CXCL2 expression was induced in endothelial cells during G-CSF-induced neutrophil mobilization. Collectively, these data suggest that CXCR2 signaling is a second chemokine axis that interacts antagonistically with CXCR4 to regulate neutrophil release from the bone marrow.
中性粒细胞是先天免疫反应的主要组成部分。它们的内环境稳定部分依赖于其从骨髓中的有调控的释放。骨髓基质细胞组成性表达趋化因子 CXCL12，通过激活其受体 CXCR4 为中性粒细胞在骨髓中的保留提供了关键信号。CXCR4 信号的减弱会导致中性粒细胞通过未知机制进入循环。我们使用 Cxcr2(-/-) 和 WT 细胞重建的混合骨髓嵌合体小鼠研究了 CXCR2 结合的 ELR+趋化因子在中性粒细胞转运中的作用。在这种情况下，缺乏 CXCR2 的中性粒细胞优先保留在骨髓中，这种表型类似于先天性骨髓角化病，其特征是慢性中性粒细胞减少症。此外，CXCR4 的短暂破坏不能动员 Cxcr2(-/-)中性粒细胞。然而，缺乏 CXCR2 和 CXCR4 的中性粒细胞表现出持续的动员，表明 CXCR4 在中性粒细胞转运中起主导作用。关于 CXCR2 配体，骨髓内皮细胞和成骨细胞组成性表达 ELR+趋化因子 CXCL1 和 CXCL2，并且在 G-CSF 诱导的中性粒细胞动员期间内皮细胞中诱导表达 CXCL2。总之，这些数据表明 CXCR2 信号是与 CXCR4 相互拮抗调节中性粒细胞从骨髓中释放的第二个趋化因子轴。
