Qiu Hui, Weng Dong, Chen Tao, Shen Li, Chen Shan-Shan, Wei Ya-Ru, Wu Qin, Zhao Meng-Meng, Li Qiu-Hong, Hu Yang, Zhang Yuan, Zhou Ying, Su Yi-Liang, Zhang Fen, Lu Li-Qin, Zhou Nian-Yu, Li Sen-Lin, Zhang Le-Le, Wang Chen, Li Hui-Ping
Department of Respiratory Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
School of Medicine, Suzhou University, Suzhou, China.
Front Immunol. 2017 Dec 11;8:1756. doi: 10.3389/fimmu.2017.01756. eCollection 2017.
The stimulator of interferon genes (STING) is a key adaptor protein mediating innate immune defense against DNA viruses. To investigate the role of STING in acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), we isolated primary peripheral blood mononuclear cells (PBMCs) from patients and healthy controls (HCs). Raw264.7 and A549 cells were infected with herpes simplex virus type 1 (HSV-1). Mice with bleomycin-induced lung fibrosis were infected with HSV-1 to stimulate acute exacerbation of the lung fibrosis. Global gene expression profiling revealed a substantial downregulation of interferon-regulated genes (downstream of STING) in the AE-IPF group compared with the HC and stable IPF groups. The PBMCs of the AE-IPF group showed significantly reduced STING protein levels, increased levels of endoplasmic reticulum (ER) stress markers, and elevated apoptosis. HSV-1 infection decreased STING expression and stimulated the ER stress pathways in Raw264.7 and A549 cells in a time- and dose-dependent manner. HSV-1 infection exacerbated the bleomycin-induced lung injury in mice. In the primary bone marrow-derived macrophages of mice treated with bleomycin and HSV-1, STING protein expression was substantially reduced; ER stress was stimulated. Tauroursodeoxycholic acid, a known inhibitor of ER stress, partially reversed those HSV-1-mediated adverse effects in mice with bleomycin-induced lung injury. STING levels in PBMCs increased after treatment in patients showing improvement but remained at low levels in patients with deterioration. Viral infection may trigger ER stress, resulting in STING deficiency and AE-IPF onset.
干扰素基因刺激物（STING）是介导针对DNA病毒的先天性免疫防御的关键衔接蛋白。为了研究STING在特发性肺纤维化急性加重（AE-IPF）中的作用，我们从患者和健康对照（HC）中分离出原代外周血单核细胞（PBMC）。用1型单纯疱疹病毒（HSV-1）感染Raw264.7和A549细胞。用博来霉素诱导肺纤维化的小鼠感染HSV-1以刺激肺纤维化的急性加重。全基因组表达谱分析显示，与HC组和稳定型IPF组相比，AE-IPF组中干扰素调节基因（STING下游）显著下调。AE-IPF组的PBMC显示STING蛋白水平显著降低，内质网（ER）应激标志物水平升高，细胞凋亡增加。HSV-1感染以时间和剂量依赖性方式降低Raw264.7和A549细胞中的STING表达并刺激ER应激途径。HSV-1感染加剧了博来霉素诱导的小鼠肺损伤。在用博来霉素和HSV-1处理的小鼠的原代骨髓来源巨噬细胞中，STING蛋白表达显著降低；刺激了ER应激。牛磺熊去氧胆酸是一种已知的ER应激抑制剂，可部分逆转博来霉素诱导的肺损伤小鼠中那些HSV-1介导的不良反应。治疗后病情改善的患者PBMC中的STING水平升高，但病情恶化的患者仍维持在低水平。病毒感染可能引发ER应激，导致STING缺乏和AE-IPF发病。
