Inhibition of the endoplasmic reticulum (ER) stress-associated IRE-1/XBP-1 pathway alleviates acute lung injury via modulation of macrophage activation

未折叠蛋白反应 内质网 炎症 巨噬细胞极化 肺泡巨噬细胞 医学 支气管肺泡灌洗 脂多糖 巨噬细胞 肿瘤坏死因子α 免疫学 癌症研究 细胞生物学 体外 生物 内科学 生物化学
作者
Yanfeng Zhao,Yan Jiang,Linsong Chen,Xinlin Zheng,Junjie Zhu,Xiao Song,Jinghan Shi,Yuping Li,Wenxin He
出处
期刊:Journal of Thoracic Disease [AME Publishing Company]
卷期号:12 (3): 284-295 被引量:31
标识
DOI:10.21037/jtd.2020.01.45
摘要

Both endoplasmic reticulum (ER) stress and macrophage diversity contribute to inflammatory processes in lung injury. However, the interaction between ER stress and macrophage M1/M2 imbalance in lung inflammation remains unclear. The present study, thus, aimed to evaluate the role of ER stress-mediated macrophage phenotype changes in lipopolysaccharide (LPS)-induced acute lung injury (ALI).Lung inflammation and injury were examined in a murine model of LPS-induced ALI with or without ER stress inhibitors. Alveolar macrophage (AM) polarization was determined by flow cytometry. Bone marrow-derived macrophages (BMDMs) were treated with either an ER stress inducer, inhibitor, or an IRE-1 endonuclease inhibitor before being polarized to an M1 and M2 phenotype. The macrophage polarization status was examined via RT-PCR and flow cytometry.Our results indicated that ER stress and IRE-1/XBP-1 signaling are activated in LPS-induced ALI. Furthermore, we observed that AM polarizes to an inflammatory phenotype upon exposure to LPS in the induction phase and an anti-inflammatory phenotype in the resolution phase of lung inflammation. Inhibition of ER stress attenuated the pathophysiological features of LPS-induced lung inflammation/injury, as evidenced by a decrease in bronchoalveolar lavage (BAL) protein levels, the number of inflammatory cells, and the expression level of inflammatory mediators. In addition, the ER stress inducer promoted M1 polarization and the switch from M2 to M1 in BMDMs, whereas inhibition of ER stress and XBP-1 splicing suppressed M1 but did not promote M2, both in vivo and in vitro.Our results demonstrated that inhibition of the ER stress-associated IRE-1/XBP-1 signaling pathway suppresses M1 polarization and ameliorates LPS-induced lung injury. This indicates that the interaction between ER stress and macrophage polarization might be a novel therapeutic target for endotoxin-induced lung inflammatory disorders.
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