The transcription factor PU.1 promotes alternative macrophage polarization and asthmatic airway inflammation
The transcription factor PU.1 promotes alternative macrophage polarization and asthmatic airway inflammation
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转录因子 PU.1 促进巨噬细胞极化和哮喘气道炎症。
DOI：
10.1093/jmcb/mjv042
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发表时间：
2015-12-01
影响因子：
5.5
通讯作者：
Christman, John W.
中科院分区：
文献类型：
--
作者：
Qian, Feng;Deng, Jing;Christman, John W.
转录因子PU.1参与巨噬细胞分化和成熟的调节。然而，PU.1在交替激活的巨噬细胞（AAM）和哮喘炎症中的作用尚未研究。在这里，我们报告说，PU.1作为一个重要的调节AAM极化，促进哮喘气道炎症的病理进展。在对尘螨、豚草和曲霉属过敏原攻击的反应中，条件性PU. 1缺陷（PU/ER（T）（+/-））小鼠表现出变应性气道炎症减弱，包括肺泡嗜酸性粒细胞浸润减少和IgE产生减少，这与粘液腺减少和杯状细胞增生有关。通过过继转移IL-4诱导的野生型（WT）巨噬细胞，PU/ER（T）（+/-）小鼠中减少的哮喘炎症得到恢复。此外，在用他莫昔芬治疗PU/ER（T）（+/-）小鼠以拯救PU. 1功能后，过敏性哮喘炎症显著恢复。体外研究表明，用IL-4处理PU. 1缺陷型巨噬细胞减弱了几丁质酶3样3（Ym-1）和抵抗素样分子α 1（Fizz-1）的表达，这两种分子是AAM极化的特异性标志物。此外，巨噬细胞中的PU.1表达响应于IL-4激发是可诱导的，这与信号转导子和转录激活子6（STAT 6）的磷酸化有关。此外，与WT小鼠相比，在致敏小鼠中的LPS攻击几乎消除了PU/ER（T）（+/-）小鼠肺组织中Ym-1和Fizz-1的基因表达。这些数据一起表明PU.1在AAM极化和哮喘炎症中起关键作用。
The transcription factor PU.1 is involved in regulation of macrophage differentiation and maturation. However, the role of PU.1 in alternatively activated macrophage (AAM) and asthmatic inflammation has yet been investigated. Here we report that PU.1 serves as a critical regulator of AAM polarization and promotes the pathological progress of asthmatic airway inflammation. In response to the challenge of DRA (dust mite, ragweed, and Aspergillus) allergens, conditional PU.1-deficient (PU/ER(T)(+/-)) mice displayed attenuated allergic airway inflammation, including decreased alveolar eosinophil infiltration and reduced production of IgE, which were associated with decreased mucous glands and goblet cell hyperplasia. The reduced asthmatic inflammation in PU/ER(T)(+/-) mice was restored by adoptive transfer of IL-4-induced wild-type (WT) macrophages. Moreover, after treating PU/ER(T)(+/-) mice with tamoxifen to rescue PU.1 function, the allergic asthmatic inflammation was significantly restored. In vitro studies demonstrate that treatment of PU.1-deficient macrophages with IL-4 attenuated the expression of chitinase 3-like 3 (Ym-1) and resistin-like molecule alpha 1 (Fizz-1), two specific markers of AAM polarization. In addition, PU.1 expression in macrophages was inducible in response to IL-4 challenge, which was associated with phosphorylation of signal transducer and activator of transcription 6 (STAT6). Furthermore, DRA challenge in sensitized mice almost abrogated gene expression of Ym-1 and Fizz-1 in lung tissues of PU/ER(T)(+/-) mice compared with WT mice. These data, all together, indicate that PU.1 plays a critical role in AAM polarization and asthmatic inflammation.