CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow
CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow
复制标题
DOI：
10.1172/jci41649
复制
发表时间：
2010-07-01
影响因子：
15.9
通讯作者：
Link, Daniel C.
中科院分区：
文献类型：
--
作者：
Eash, Kyle J.;Greenbaum, Adam M.;Link, Daniel C.
中性粒细胞是先天免疫反应的主要成分。它们的体内平衡部分地通过从骨髓中调节中性粒细胞的释放来维持。趋化因子CXCL 12通过骨髓基质细胞的组成型表达通过其受体CXCR 4的活化为骨髓中的中性粒细胞提供关键的滞留信号。CXCR 4信号传导的减弱导致中性粒细胞通过未知机制进入循环。我们研究了CXCR 2结合ELR+趋化因子在中性粒细胞运输中的作用，使用Cxcr 2（-/-）和WT细胞重建的小鼠混合骨髓嵌合体。在这种情况下，缺乏CXCR 2的中性粒细胞优先保留在骨髓中，这是一种类似于先天性疾病骨髓增生异常的表型，其特征在于慢性中性粒细胞减少症。此外，CXCR 4的短暂破坏未能动员Cxcr 2（-/-）中性粒细胞。然而，缺乏CXCR 2和CXCR 4的中性粒细胞显示组成性动员，表明CXCR 4在中性粒细胞运输中起主导作用。关于CXCR 2配体，骨髓内皮细胞和成骨细胞组成性表达ELR+趋化因子CXCL 1和CXCL 2，并且在G-CSF诱导的中性粒细胞动员期间在内皮细胞中诱导CXCL 2表达。总的来说，这些数据表明CXCR 2信号传导是第二个趋化因子轴，其与CXCR 4拮抗地相互作用以调节中性粒细胞从骨髓中释放。
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.