Down-regulation of the forkhead transcription factor Foxp1 is required for monocyte differentiation and macrophage function
Down-regulation of the forkhead transcription factor Foxp1 is required for monocyte differentiation and macrophage function
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DOI：
10.1182/blood-2008-01-137018
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发表时间：
2008-12-01
期刊：
影响因子：
20.3
通讯作者：
Simon, Daniel I.
中科院分区：
文献类型：
--
作者：
Shi, Can;Sakuma, Masashi;Simon, Daniel I.
通过整合素参与下调叉头转录因子Foxp 1控制体外单核细胞分化为了确定Foxp 1是否在体内单核细胞分化和巨噬细胞功能中起关键作用，我们使用CD 68启动子在单核细胞/巨噬细胞谱系细胞中产生过表达人FOXP 1的转基因小鼠（macFoxp 1 tg）。macFoxp 1 tg小鼠的循环血液单核细胞巨噬细胞集落刺激因子受体（c-Fms/M-CSFR）表达降低，迁移能力受损，并减少作为脾巨噬细胞的蓄积。与野生型细胞相比，macFoxp 1 tg中的巨噬细胞功能，包括细胞因子产生、吞噬作用和呼吸爆发，在整体上受损。破骨细胞生成和骨吸收活性也减弱macFoxp 1 tg小鼠。在化学性和细菌性腹膜炎模型中，macFoxp 1 tg小鼠表现出巨噬细胞蓄积、细菌清除和存活率降低。c-Fms/M-CSFR的过度表达逆转了macFoxp 1 tg巨噬细胞中细胞因子的产生和吞噬功能的缺陷，表明c-Fms/M-CSFR的抑制可能是Foxp 1在单核细胞分化和巨噬细胞功能中起作用的主要机制。综上所述，这些观察结果确定下调Foxp 1作为关键的单核细胞分化和巨噬细胞的功能在体内。（血。2008; 112：4699-4711）
Down-regulation of the forkhead transcription factor Foxp1 by integrin engagement controls monocyte differentiation in vitro. To determine whether Foxp1 plays a critical role in monocyte differentiation and macrophage functions in vivo, we generated transgenic mice (macFoxp1tg) overexpressing human FOXP1 in monocyte/macrophage lineage cells using the CD68 promoter. Circulating blood monocytes from macFoxp1tg mice have reduced expression of the receptor for macrophage colony-stimulating factor (c-Fms/M-CSFR), impaired migratory capacity, and diminished accumulation as splenic macrophages. Macrophage functions, including cytokine production, phagocytosis, and respiratory burst were globally impaired in macFoxp1tg compared with wild-type cells. Osteoclastogenesis and bone resorption activity were also attenuated in macFoxp1tg mice. In models of chemical and bacterial peritonitis, macFoxp1tg mice exhibited reduced macrophage accumulation, bacterial clearance, and survival. Enforced overexpression of c-Fms/M-CSFR reversed the cytokine production and phagocytosis defects in macFoxp1tg macrophages, indicating that repression of c-fms/M-CSFR is likely the dominant mechanism responsible for Foxp1 action in monocyte differentiation and macrophage function. Taken together, these observations identify down-regulation of Foxp1 as critical for monocyte differentiation and macrophage functions in vivo. (Blood. 2008; 112: 4699-4711)