Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
J Exp Med. 2013 Mar 11;210(3):551-61. doi: 10.1084/jem.20120260. Epub 2013 Feb 11.
Pulmonary Staphylococcus aureus (SA) infections are a public health concern and a major complication of hyper-IgE syndrome, caused by mutations in STAT3. In contrast to previous findings of skin infection, we observed that clearance of SA from the lung did not require T, B, or NK cells but did require Stat3 activation. Immunohistochemistry showed robust Stat3 phosphorylation in the lung epithelium. We identified that a critical Stat3 target gene in lung epithelium is Reg3g (regenerating islet-derived 3 γ), a gene which is highly expressed in gastrointestinal epithelium but whose role in pulmonary host defense is uncharacterized. Stat3 regulated Reg3g transcription through direct binding at the Reg3g promoter region. Recombinant Reg3γ bound to SA and had both bacteriostatic and bactericidal activity in a dose-dependent fashion. Stat3 inhibition in vivo reduced Reg3g transcripts in the lung, and more importantly, recombinant Reg3γ rescued mice from defective SA clearance. These findings reveal an antibacterial function for lung epithelium through Stat3-mediated induction of Reg3γ.
肺部金黄色葡萄球菌（SA）感染是一个公共卫生关注点，也是高免疫球蛋白 E 综合征的主要并发症，由 STAT3 突变引起。与先前发现的皮肤感染不同，我们观察到清除肺部的 SA 不需要 T、B 或 NK 细胞，但确实需要 Stat3 激活。免疫组织化学显示肺上皮细胞中有强烈的 Stat3 磷酸化。我们确定肺上皮细胞中 Stat3 的一个关键靶基因是 Reg3g（再生胰岛衍生 3γ），该基因在胃肠道上皮细胞中高度表达，但在肺部宿主防御中的作用尚未确定。Stat3 通过直接结合 Reg3g 启动子区域来调节 Reg3g 转录。重组 Reg3γ 与 SA 结合，并以剂量依赖的方式具有抑菌和杀菌活性。体内 Stat3 抑制减少了肺中的 Reg3g 转录物，更重要的是，重组 Reg3γ 挽救了因清除 SA 缺陷而导致的小鼠。这些发现揭示了通过 Stat3 介导的 Reg3γ 诱导，肺上皮细胞具有抗菌功能。
