PU.1 regulation of human alveolar macrophage differentiation requires granulocyte-macrophage colony-stimulating factor
PU.1 regulation of human alveolar macrophage differentiation requires granulocyte-macrophage colony-stimulating factor
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DOI：
10.1152/ajplung.00216.2003
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发表时间：
2003-11-01
影响因子：
4.9
通讯作者：
Thomassen, MJ
中科院分区：
文献类型：
--
作者：
Bonfield, TL;Raychaudhuri, B;Thomassen, MJ
粒细胞巨噬细胞集落刺激因子（GM-CSF）在GM-CSF敲除小鼠模型中与肺稳态密切相关。这些动物出现孤立的肺部病变，类似于人类的肺泡蛋白沉积症（PAP）。成人肺泡蛋白沉积症的发展不是由于缺乏GM-CSF基因或受体缺陷，而是由于抗GM-CSF自身免疫的发展。GM-CSF在PAP发展中的作用尚不清楚。对GM-CSF敲除小鼠的研究表明，肺泡巨噬细胞中PU.1蛋白表达的缺乏与成熟、分化和表面活性剂分解代谢的减少有关。本研究探讨了人PAP肺泡巨噬细胞中PU.1的体内外表达及GM-CSF对PU.1的调节作用。我们首次发现PAP支气管肺泡灌洗细胞中PU.1 mRNA表达与健康对照相比不足。pu .1依赖性终末分化标志物CD32 （FCgammaII）、甘露糖受体和巨噬细胞集落刺激因子受体（M-CSFR）在PAP肺泡巨噬细胞中减少。体外研究表明，外源性GMCSF处理上调PAP肺泡巨噬细胞PU.1和M-CSFR基因表达。最后，体内研究表明，与健康对照组和未接受GM-CSF治疗的PAP患者相比，接受GM-CSF治疗的PAP患者肺泡巨噬细胞中PU.1和M-CSFR的表达水平更高。这些观察结果表明，PU.1在人肺泡巨噬细胞的终末分化中起关键作用。
Granulocytemacrophage colony-stimulating factor (GM-CSF) is critically implicated in lung homeostasis in the GM-CSF knockout mouse model. These animals develop an isolated lung lesion reminiscent of pulmonary alveolar proteinosis (PAP) seen in humans. The development of the adult form of human alveolar proteinosis is not due to the absence of a GM-CSF gene or receptor defect but to the development of an anti-GM-CSF autoimmunity. The role of GM-CSF in the development of PAP is unknown. Studies in the GM-CSF knockout mouse have shown that lack of PU.1 protein expression in alveolar macrophages is correlated with decreased maturation, differentiation, and surfactant catabolism. This study investigates PU.1 expression in vitro and in vivo in human PAP alveolar macrophages as well as the regulation of PU.1 by GM-CSF. We show for the first time that PU.1 mRNA expression in PAP bronchoalveolar lavage cells is deficient compared with healthy controls. PU.1-dependent terminal differentiation markers CD32 (FCgammaII), mannose receptor, and macrophage colony-stimulating factor receptor (M-CSFR) are decreased in PAP alveolar macrophages. In vitro studies demonstrate that exogenous GMCSF treatment upregulated PU.1 and M-CSFR gene expression in PAP alveolar macrophages. Finally, in vivo studies showed that PAP patients treated with GM-CSF therapy have higher levels of PU.1 and M-CSFR expression in alveolar macrophages compared with healthy control and PAP patients before GM-CSF therapy. These observations suggest that PU.1 is critical in the terminal differentiation of human alveolar macrophages.