Honczarenko Marek, Ratajczak Mariusz Z, Nicholson-Weller Anne, Silberstein Leslie E
Joint Program in Transfusion Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 2005 Sep 15;175(6):3698-706. doi: 10.4049/jimmunol.175.6.3698.
Complement C3a promotes CXCL12-induced migration and engraftment of human and murine hemopoietic progenitor cells, suggesting a cross-influence between anaphylatoxin and chemokine axes. Here we have explored the underlying mechanism(s) of complement anaphylatoxin and chemokine cooperation. In addition to C3a, C3a-desArg and C4a but not C5a, are potent enhancers of CXCL12-induced chemotaxis of human and murine bone marrow (BM) stem/progenitor cells and B lineage cells. C3a enhancement of chemotaxis is chemokine specific because it is also observed for chemotaxis to CCL19 but not to CXCL13. The potentiating effect of C3a on CXCL12 is independent of the classical C3a receptor (C3aR). First, human BM CD34(+) and B lineage cells do not express C3aR by flow cytometry. Second, the competitive C3aR inhibitor SB290157 does not affect C3a-mediated enhancement of CXCL12-induced chemotaxis. Third, enhancement of chemotaxis of hemopoietic cells is also mediated by C3a-desArg, which does not bind to C3aR. Finally, C3a enhances CXCL12-induced chemotaxis of BM cells from C3aR knockout mice similar to BM cells from wild-type mice. Subsequent studies revealed that C3a increased the binding affinity of CXCL12 to human CXCR4(+)/C3aR(-), REH pro-B cells, which is compatible with a direct interaction between C3a and CXCL12. BM stromal cells were able to generate C3a, C3a-desArg, C4a, as well as CXCL12, suggesting that this pathway could function in vivo. Taken together, we demonstrate a C3a-CXCL12 interaction independent of the C3aR, which may provide a mechanism to modulate the function of CXCL12 in the BM microenvironment.
补体C3a促进CXCL12诱导的人和小鼠造血祖细胞的迁移与植入，提示过敏毒素和趋化因子轴之间存在交叉影响。在此，我们探究了补体过敏毒素与趋化因子协同作用的潜在机制。除C3a外，C3a-去精氨酸和C4a（而非C5a）是CXCL12诱导的人和小鼠骨髓（BM）干/祖细胞及B淋巴细胞趋化性的强效增强剂。C3a对趋化性增强具有趋化因子特异性，因为对CCL19诱导的趋化性也有增强作用，但对CXCL13诱导的趋化性则无此作用。C3a对CXCL12的增强作用不依赖于经典的C3a受体（C3aR）。首先，人BM CD34(+)细胞和B淋巴细胞通过流式细胞术检测不表达C3aR。其次，竞争性C3aR抑制剂SB290157不影响C3a介导的CXCL12诱导趋化性的增强。第三，造血细胞趋化性的增强也由C3a-去精氨酸介导，其不与C3aR结合。最后，C3a增强CXCL12诱导的C3aR基因敲除小鼠BM细胞的趋化性，与野生型小鼠的BM细胞相似。后续研究表明，C3a增加了CXCL12与人CXCR4(+)/C3aR(-)的REH前B细胞的结合亲和力，这与C3a和CXCL12之间的直接相互作用一致。BM基质细胞能够产生C3a、C3a-去精氨酸、C4a以及CXCL12，提示该途径可能在体内发挥作用。综上所述，我们证明了一种不依赖C3aR的C3a-CXCL12相互作用，这可能为调节BM微环境中CXCL12的功能提供一种机制。
