Basu Sunanda, Broxmeyer Hal E
Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Research Institute No. 2 Building, Room 302, 950 West Walnut Street, Indianapolis, IN 46202, USA.
J Immunol. 2009 Dec 1;183(11):7478-88. doi: 10.4049/jimmunol.0900542. Epub 2009 Nov 16.
CXCL12 and its receptor CXCR4 play an important role in hematopoietic stem/progenitor cell (HSPC) migration from and retention within the bone marrow. HSPCs are very selective in their chemotactic response and undergo chemotaxis only in response to CXCL12. In addition to CXCR4, HSPCs express receptors for various other chemokines; however, the role of these receptors is not well understood. Freshly isolated CD34(+) cells (highly enriched for HSPCs) from cord blood (CB) express low levels of CCR5; however, if the cells were washed with acidic buffer before Ab staining to remove any ligand bound to CCR5, then nearly 80% of CD34(+) CB cells were found to express CCR5 on the cell surface. Although none of the CCR5 ligands investigated in this study (CCL3, CCL4, and CCL5) induced chemotaxis, at relatively high concentrations they transiently enhanced CXCL12-mediated chemotaxis of CD34(+) CB cells. In contrast, CXCL12-mediated adhesion of cells to VCAM-1-coated surfaces was reduced if CD34(+) CB cells were pretreated with these CCR5 ligands for 15 min. The effect of these chemokines on CXCL12-mediated responses was not at the level of CXCR4 expression, but on downstream signaling pathways elicited by CXCL12. Pretreatment with CCR5 chemokines enhanced CXCL12-mediated Akt phosphorylation, but down-modulated calcium flux in CD34(+) CB cells. Modulation of CXCL12-mediated responses of CD34(+) cells by CCR5 chemokines provides a possible mechanism that underlies movement of HSPCs during inflammation.
CXCL12及其受体CXCR4在造血干/祖细胞（HSPC）从骨髓迁出及在骨髓内滞留过程中发挥重要作用。HSPC对趋化反应具有高度选择性，仅对CXCL12产生趋化作用。除CXCR4外，HSPC还表达多种其他趋化因子的受体；然而，这些受体的作用尚未完全明确。从脐带血（CB）中新鲜分离的CD34(+)细胞（高度富集HSPC）表达低水平的CCR5；然而，如果在抗体染色前用酸性缓冲液洗涤细胞以去除与CCR5结合的任何配体，则发现近80%的CD34(+) CB细胞在细胞表面表达CCR5。尽管本研究中所研究的CCR5配体（CCL3、CCL4和CCL5）均未诱导趋化作用，但在相对较高浓度下，它们可短暂增强CXCL12介导的CD34(+) CB细胞趋化作用。相反，如果用这些CCR5配体预处理CD34(+) CB细胞15分钟，则CXCL12介导的细胞与VCAM-1包被表面的黏附会降低。这些趋化因子对CXCL12介导反应的影响并非在CXCR4表达水平，而是在CXCL12引发的下游信号通路水平。用CCR5趋化因子预处理可增强CXCL12介导的Akt磷酸化，但下调CD34(+) CB细胞中的钙流。CCR5趋化因子对CD34(+)细胞CXCL12介导反应的调节提供了一种可能的机制，该机制是HSPC在炎症期间移动的基础。
