The role of the CCL2/CCR2 axis in mouse mast cell migration in vitro and in vivo.
The role of the CCL2/CCR2 axis in mouse mast cell migration in vitro and in vivo.
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DOI：
10.4049/jimmunol.0904177
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发表时间：
2010-06-01
期刊：
影响因子：
--
通讯作者：
Weller CL
中科院分区：
文献类型：
--
作者：
Collington SJ;Hallgren J;Pease JE;Jones TG;Rollins BJ;Westwick J;Austen KF;Williams TJ;Gurish MF;Weller CL
组织驻留肥大细胞（MCs）在过敏性疾病中具有重要作用。在过敏性气道炎症的小鼠模型中，细支气管周围肥大细胞的增加与肺灌洗液中趋化因子CCL2浓度的升高有关。骨髓（BM）中产生的肥大细胞祖细胞（MCps）通过跨内皮迁移被募集到组织中，并且我们发现CCL2在体外对新鲜分离的骨髓中的肥大细胞祖细胞具有趋化作用。在白细胞介素 - 3（IL - 3）+干细胞因子（SCF）中培养时，未成熟但不是成熟的骨髓来源的肥大细胞会响应CCL2发生迁移，而仅在IL - 3中培养时则不会。然而，在这两种培养条件下的细胞都表达CCL2受体CCR2的mRNA，并且以相似的亲和力结合放射性标记的趋化因子，这突出了SCF作为将CCR2与下游事件偶联的关键介质的作用，最终导致趋化作用。当通过静脉注射给予在IL - 3 + SCF培养条件下的未成熟骨髓来源的肥大细胞时，它们会在体内注射CCL2的皮肤部位聚集。在CCR2 - / - 和CCL2 - / - 小鼠品系中，肥大细胞祖细胞向过敏原致敏/激发的肺的募集显著减少。然而，对亚致死剂量照射并进行骨髓重建的小鼠的重建研究表明，骨髓细胞和基质成分都可以提供CCL2，而CCR2的功能存在于基质成分而非骨髓细胞中。这些实验揭示了SCF在趋化因子受体偶联中的一种新功能，但也表明CCL2/CCR2轴在肺部炎症期间募集肥大细胞祖细胞中具有复杂的作用。
Tissue-resident mast cells (MCs) are important in allergic diseases. In a mouse model of allergic airways inflammation, an increase in peribronchiolar MCs was associated with increased concentrations of the chemokine CCL2 in lung lavage. MC progenitors (MCps) arising in bone marrow (BM) are recruited to tissues by transendothelial migration, and we found that CCL2 is chemotactic for MCps in freshly isolated BM in vitro. Immature, but not mature, BM-derived MCs migrated in response to CCL2 when cultured in IL-3+stem cell factor (SCF) but not when cultured in IL-3 alone. However, the cells under both culture conditions expressed mRNA for CCR2, the receptor for CCL2, and bound the radiolabeled chemokine with similar affinities, highlighting SCF as a key mediator in coupling CCR2 to downstream events, culminating in chemotaxis. Immature BM-derived MCs from IL-3 +SCF cultures, when administered i.v., accumulated at skin sites injected with CCL2 in vivo. MCp recruitment to the allergen-sensitized/challenged lung was significantly reduced in CCR2−/− and CCL2−/− mouse strains. However, reconstitution studies of sublethally irradiated and BM-reconstituted mice indicated that BM cells and stromal elements could provide CCL2, whereas the CCR2 function resided with stromal elements rather than BM cells. These experiments revealed a new function of SCF in chemokine receptor coupling, but they suggest a complex role of the CCL2/CCR2 axis in recruiting MCps during pulmonary inflammation.
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