S100A4 regulates macrophage chemotaxis.

S100A4 regulates macrophage chemotaxis.
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DOI:
10.1091/mbc.e09-07-0609
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发表时间:
2010-08-01
影响因子:
3.3
通讯作者:
Bresnick AR
Bresnick AR
中科院分区:
生物学3区
文献类型:
--
作者:
Li ZH;Dulyaninova NG;House RP;Almo SC;Bresnick AR

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使用有针对性的基因缺失,我们表明,S100 A4转移因子是所需的巨噬细胞招聘到炎症部位在体内。S100 A4 −/−原代巨噬细胞由于肌球蛋白IIA过度组装和CSF-1受体信号传导改变而表现出趋化性缺陷。这些研究确立了S100 A4作为巨噬细胞运动的调节剂。S100 A4是钙结合蛋白S100家族的成员,直接参与肿瘤转移。除了在肿瘤细胞中表达外,S100 A4还在正常细胞和组织中表达,包括成纤维细胞和免疫系统细胞。为了研究S100 A4对正常生理的贡献,我们通过基因打靶建立了S100 A4缺陷小鼠。纯合子S100 A4 −/−小鼠可生育,生长正常,没有明显的异常;然而,S100 A4的缺失导致巨噬细胞在体内炎症部位的募集受损。与这些观察结果相一致,来自S100 A4 −/−小鼠的原代骨髓巨噬细胞(BMPs)在体外表现出趋化运动缺陷。S100 A4 −/− Bp 53形成不稳定的突起,过度组装肌球蛋白-IIA,并表现出改变的集落刺激因子-1受体信号传导。这些研究确立了S100 A4作为生理巨噬细胞运动的调节剂,并证明S100 A4介导体内巨噬细胞募集和趋化性。
Using a targeted genetic deletion, we show that the S100A4 metastasis factor is required for macrophage recruitment to sites of inflammation in vivo. S100A4−/− primary macrophages display defects in chemotaxis due to myosin-IIA overassembly and altered CSF-1 receptor signaling. These studies establish S100A4 as a regulator of macrophage motility. S100A4, a member of the S100 family of Ca2+-binding proteins, is directly involved in tumor metastasis. In addition to its expression in tumor cells, S100A4 is expressed in normal cells and tissues, including fibroblasts and cells of the immune system. To examine the contribution of S100A4 to normal physiology, we established S100A4-deficient mice by gene targeting. Homozygous S100A4−/− mice are fertile, grow normally and exhibit no overt abnormalities; however, the loss of S100A4 results in impaired recruitment of macrophages to sites of inflammation in vivo. Consistent with these observations, primary bone marrow macrophages (BMMs) derived from S100A4−/− mice display defects in chemotactic motility in vitro. S100A4−/− BMMs form unstable protrusions, overassemble myosin-IIA, and exhibit altered colony-stimulating factor-1 receptor signaling. These studies establish S100A4 as a regulator of physiological macrophage motility and demonstrate that S100A4 mediates macrophage recruitment and chemotaxis in vivo.
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