Hu Rong, Chen Zhi-Feng, Yan Jia, Li Qi-Fang, Huang Yan, Xu Hui, Zhang Xiao-Ping, Jiang Hong
Department of Anesthesiology, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China;
Institute of Intervention Vessel, Tongji University, Shanghai 200092, China; and Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
J Immunol. 2015 Nov 15;195(10):4802-9. doi: 10.4049/jimmunol.1500073. Epub 2015 Oct 16.
Diverse clinical factors, including intestinal ischemia, contribute to acute lung injury (ALI), which has up to a 40% mortality rate. During the development of lung injury an immune response is elicited that exacerbates the lung insult. Neutrophils have been well studied in mediating the pulmonary insults through an assortment of mechanisms, such as release of granule contents and production of proinflammatory cytokines due to the overactivation of complement and cytokines. In this study, we found that enhanced endoplasmic reticulum (ER) stress was observed in infiltrated neutrophils in the early stage of an ALI mice model. In neutrophils, complement 5a (C5a) inspires strong ER stress through inositol-requiring kinase 1a and, to a less extent, the protein kinase R-like ER kinase signaling pathway. The granule release induced by C5a was ER stress mediated. Knowkdown of X-box-binding protein 1, a downstream signaling molecule of inositol-requiring kinase 1a, impaired granule release, based on myeloperoxidase production. Further analysis revealed that C5a induced ER stress by binding to C5a receptor in neutrophils. Using xbp(f/f) MRP8-cre mice in which X-box-binding protein 1 is deficient specifically in neutrophils and ER stress is deprived, we confirmed that ER stress in neutrophils was required for granule release in vivo and led to ALI, whereas dampening ER stress in neutrophils substantially alleviated ALI. Taken together, our results demonstrated that C5a receptor-mediated ER stress induced granule release in neutrophils, contributing to the development of ALI. This novel mechanism suggests a new potential therapeutic target in autophagy regulation for ALI.
多种临床因素，包括肠道缺血，均可导致急性肺损伤（ALI），其死亡率高达40%。在肺损伤的发展过程中，会引发免疫反应，从而加剧肺部损伤。中性粒细胞通过多种机制介导肺部损伤，这方面已得到充分研究，比如由于补体和细胞因子过度激活而释放颗粒内容物并产生促炎细胞因子。在本研究中，我们发现在ALI小鼠模型早期，浸润的中性粒细胞中内质网（ER）应激增强。在中性粒细胞中，补体5a（C5a）通过肌醇需求激酶1a，并在较小程度上通过蛋白激酶R样内质网激酶信号通路引发强烈的内质网应激。C5a诱导的颗粒释放是由内质网应激介导的。基于髓过氧化物酶的产生，敲低肌醇需求激酶1a的下游信号分子X盒结合蛋白1会损害颗粒释放。进一步分析表明，C5a通过与中性粒细胞中的C5a受体结合诱导内质网应激。使用xbp(f/f) MRP8-cre小鼠（其中X盒结合蛋白1在中性粒细胞中特异性缺失且内质网应激被消除），我们证实中性粒细胞中的内质网应激是体内颗粒释放所必需的，并导致ALI，而减轻中性粒细胞中的内质网应激可显著减轻ALI。综上所述，我们的结果表明C5a受体介导的内质网应激诱导中性粒细胞颗粒释放，促进ALI的发展。这一新机制提示了ALI自噬调节中的一个新的潜在治疗靶点。
