CCR2 inhibition sequesters multiple subsets of leukocytes in the bone marrow.
CCR2 inhibition sequesters multiple subsets of leukocytes in the bone marrow.
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DOI：
10.1038/srep11664
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发表时间：
2015-07-24
影响因子：
4.6
通讯作者：
Dalman RL
中科院分区：
文献类型：
--
作者：
Fujimura N;Xu B;Dalman J;Deng H;Aoyama K;Dalman RL
趋化因子受体CCR 2介导单核细胞从骨髓（BM）动员并随后迁移到靶组织中。CCR 2在白细胞亚群中差异表达的程度以及CCR 2对这些白细胞从BM动员的贡献知之甚少。使用红色荧光蛋白CCR 2报告小鼠，我们发现不同组织中白细胞亚群之间CCR 2表达的异质性。在所有组织中，炎症单核细胞、树突状细胞、浆细胞样树突状细胞和NK细胞均高度表达CCR 2。出乎意料的是，超过60%的中性粒细胞表达CCR 2，尽管水平较低。与其他组织相比，T细胞、B细胞和NK T细胞中的CCR 2表达在BM中最大。遗传性CCR 2缺陷显著隔离了BM中的所有白细胞亚群，在外周血和脾脏中观察到相互减少。通过用CCR 2信号传导抑制剂丙锗处理CCR 2抑制产生类似的效果。锗还减轻了脂多糖诱导的BM白细胞排出。与其功能意义一致，CCR 2抗体染色显示BM中性粒细胞亚群内的表面CCR 2表达。这些结果证明了CCR 2在介导白细胞从BM动员中发挥的核心作用，并表明CCR 2抑制在管理单核细胞/巨噬细胞介导的慢性炎症性病症中的作用。
Chemokine receptor CCR2 mediates monocyte mobilization from the bone marrow (BM) and subsequent migration into target tissues. The degree to which CCR2 is differentially expressed in leukocyte subsets, and the contribution of CCR2 to these leukocyte mobilization from the BM are poorly understood. Using red fluorescence protein CCR2 reporter mice, we found heterogeneity in CCR2 expression among leukocyte subsets in varying tissues. CCR2 was highly expressed by inflammatory monocytes, dendritic cells, plasmacytoid dendritic cells and NK cells in all tissues. Unexpectedly, more than 60% of neutrophils expressed CCR2, albeit at low levels. CCR2 expression in T cells, B cells and NK T cells was greatest in the BM compared to other tissues. Genetic CCR2 deficiency markedly sequestered all leukocyte subsets in the BM, with reciprocal reduction noted in the peripheral blood and spleen. CCR2 inhibition via treatment with CCR2 signaling inhibitor propagermanium produced similar effects. Propagermanium also mitigated lipopolysaccharide-induced BM leukocyte egress. Consistent with its functional significance, CCR2 antibody staining revealed surface CCR2 expression within a subset of BM neutrophils. These results demonstrate the central role CCR2 plays in mediating leukocyte mobilization from the BM, and suggest a role for CCR2 inhibition in managing monocytes/macrophages-mediated chronic inflammatory conditions.