Localized CCR2 Activation in the Bone Marrow Niche Mobilizes Monocytes by Desensitizing CXCR4.
Localized CCR2 Activation in the Bone Marrow Niche Mobilizes Monocytes by Desensitizing CXCR4.
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DOI：
10.1371/journal.pone.0128387
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Miller RJ
中科院分区：
文献类型：
--
作者：
Jung H;Mithal DS;Park JE;Miller RJ
存在于骨髓中的炎性（经典）单核细胞必须进入血流以对抗微生物感染。这些单核细胞表达高水平的CCR2，这是一种趋化因子受体，其激活是它们离开骨髓所必需的。CCR2如何在骨髓中局部激活以及它们的激活如何促进单核细胞排出尚不清楚。在这里，我们使用了双转基因株系，可以在体内观察到CCR2的激活，并表明其趋化因子配体CCL2是由骨髓中的基质细胞急性释放的，这些基质细胞与CCR2表达的单核细胞直接接触。这些单核细胞也表达CXCR4，其活化使骨髓中的细胞固定，并且与表达CXCL12（CXCR4配体）的基质细胞接触。在炎症反应期间，CCL2被释放并激活邻近单核细胞上的CCR2。我们证明，急性分离的骨髓细胞共表达CCR2和CXCR4，CCR2激活脱敏CXCR4。在小鼠中通过特异性受体拮抗剂抑制CXCR4导致CCR2表达细胞在没有炎性损伤的情况下离开骨髓。总之，这些结果表明了一种新的机制，其中骨髓中单核细胞上的CCR 2的局部活化减弱了由相同细胞表达的CXCR 4提供的锚定信号传导，并将骨髓单核细胞动员到血流中。我们的研究结果还提供了一个可推广的模型，即趋化因子受体的交叉脱敏通过整合多种趋化因子信号来微调细胞迁移率。
Inflammatory (classical) monocytes residing in the bone marrow must enter the bloodstream in order to combat microbe infection. These monocytes express high levels of CCR2, a chemokine receptor whose activation is required for them to exit the bone marrow. How CCR2 is locally activated in the bone marrow and how their activation promotes monocyte egress is not understood. Here, we have used double transgenic lines that can visualize CCR2 activation in vivo and show that its chemokine ligand CCL2 is acutely released by stromal cells in the bone marrow, which make direct contact with CCR2-expressing monocytes. These monocytes also express CXCR4, whose activation immobilizes cells in the bone marrow, and are in contact with stromal cells expressing CXCL12, the CXCR4 ligand. During the inflammatory response, CCL2 is released and activates the CCR2 on neighboring monocytes. We demonstrate that acutely isolated bone marrow cells co-express CCR2 and CXCR4, and CCR2 activation desensitizes CXCR4. Inhibiting CXCR4 by a specific receptor antagonist in mice causes CCR2-expressing cells to exit the bone marrow in absence of inflammatory insults. Taken together, these results suggest a novel mechanism whereby the local activation of CCR2 on monocytes in the bone marrow attenuates an anchoring signalling provided by CXCR4 expressed by the same cell and mobilizes the bone marrow monocyte to the blood stream. Our results also provide a generalizable model that cross-desensitization of chemokine receptors fine-tunes cell mobility by integrating multiple chemokine signals.
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影响因子：
20.3
作者：
Liu, Qian;Chen, Haoqian;McDermott, David H.
通讯作者：
McDermott, David H.
影响因子：
15.3
作者：
BISCHOFF, SC;KRIEGER, M;DAHINDEN, CA
通讯作者：
DAHINDEN, CA
影响因子：
5.3
作者：
Dzenko, KA;Andjelkovic, AV;Pachter, JS
通讯作者：
Pachter, JS
影响因子：
32.4
作者：
Ara, T;Tokoyoda, K;Nagasawa, T
通讯作者：
Nagasawa, T
DOI：
10.1523/jneurosci.0485-09.2009
发表时间：
2009-06-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Jung H;Bhangoo S;Banisadr G;Freitag C;Ren D;White FA;Miller RJ
通讯作者：
Miller RJ