Neutropenia with impaired host defense against microbial infection in mice lacking androgen receptor.
Neutropenia with impaired host defense against microbial infection in mice lacking androgen receptor.
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DOI：
10.1084/jem.20082521
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发表时间：
2009-05-11
期刊：
影响因子：
--
通讯作者：
Chang C
中科院分区：
文献类型：
--
作者：
Chuang KH;Altuwaijri S;Li G;Lai JJ;Chu CY;Lai KP;Lin HY;Hsu JW;Keng P;Wu MC;Chang C
中性粒细胞是形成抵抗微生物感染的细胞介导防御的第一线的主要吞噬细胞，其在骨髓中产生并响应于粒细胞集落刺激因子（G-CSF）而释放到循环中。在这里，我们报告，雄激素受体敲除（ARKO）小鼠是血小板减少症，对急性细菌感染敏感，而阉割只导致中度中性粒细胞减少的小鼠和人类。雄激素补充剂可以通过稳定去势小鼠的AR来恢复中性粒细胞计数，但在ARKO和睾丸雌性化突变（Tfm）小鼠中则不然。我们的研究结果表明，AR基因的缺失不影响髓系定型，但显着降低了中性粒细胞前体细胞的增殖活性，并延缓中性粒细胞的成熟。与野生型对照相比，ARKO中性粒细胞中CXCR 2依赖性迁移也减少。G-CSF不能延迟ARKO中性粒细胞的凋亡，并且ARKO小鼠对外源性G-CSF注射表现出较差的粒细胞生成反应。此外，AR可在转导入ARKO祖细胞后恢复G-CSF依赖性粒细胞分化。我们进一步发现，AR通过激活细胞外信号调节激酶1/2以及通过减少PIAS 3与Stat 3的抑制性结合来维持Stat 3活性来增强G-CSF信号传导。总的来说，我们的研究结果表明AR在粒细胞生成和宿主防御微生物感染中起着重要作用。
Neutrophils, the major phagocytes that form the first line of cell-mediated defense against microbial infection, are produced in the bone marrow and released into the circulation in response to granulocyte-colony stimulating factor (G-CSF). Here, we report that androgen receptor knockout (ARKO) mice are neutropenic and susceptible to acute bacterial infection, whereas castration only results in moderate neutrophil reduction in mice and humans. Androgen supplement can restore neutrophil counts via stabilizing AR in castrated mice, but not in ARKO and testicular feminization mutant (Tfm) mice. Our results show that deletion of the AR gene does not influence myeloid lineage commitment, but significantly reduces the proliferative activity of neutrophil precursors and retards neutrophil maturation. CXCR2-dependent migration is also decreased in ARKO neutrophils as compared with wild-type controls. G-CSF is unable to delay apoptosis in ARKO neutrophils, and ARKO mice show a poor granulopoietic response to exogenous G-CSF injection. In addition, AR can restore G-CSF–dependent granulocytic differentiation upon transduction into ARKO progenitors. We further found that AR augments G-CSF signaling by activating extracellular signal-regulated kinase 1/2 and also by sustaining Stat3 activity via diminishing the inhibitory binding of PIAS3 to Stat3. Collectively, our findings demonstrate an essential role for AR in granulopoiesis and host defense against microbial infection.
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影响因子：
2.4
作者：
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通讯作者：
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缺乏N-甲基肽受体的小鼠中抗菌宿主防御受损。
影响因子：
15.3
作者：
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作者：
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