Endoplasmic Reticulum Stress of Neutrophils Is Required for Ischemia/Reperfusion-Induced Acute Lung Injury
Endoplasmic Reticulum Stress of Neutrophils Is Required for Ischemia/Reperfusion-Induced Acute Lung Injury
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DOI：
10.4049/jimmunol.1500073
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发表时间：
2015-11-15
影响因子：
4.4
通讯作者：
Jiang, Hong
中科院分区：
文献类型：
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作者：
Hu, Rong;Chen, Zhi-Feng;Jiang, Hong
多种临床因素，包括肠缺血，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，引发了一种加剧肺损伤的免疫反应。中性粒细胞通过多种机制介导肺损伤，如颗粒内容物的释放和由于补体和细胞因子的过度激活而产生的促炎细胞因子，已经得到了很好的研究。在本研究中，我们发现ALI小鼠模型早期浸润的中性粒细胞内质网（ER）应激增强。在中性粒细胞中，补体5a （C5a）通过肌醇要求激酶1a激发强烈的内质网应激，并在较小程度上通过蛋白激酶r样内质网激酶信号通路。C5a诱导的颗粒释放是内质网应激介导的。x -box结合蛋白1（肌醇要求激酶1a的下游信号分子）的下调，导致基于髓过氧化物酶产生的颗粒释放受损。进一步分析发现，C5a通过与中性粒细胞中的C5a受体结合诱导内质网应激。使用中性粒细胞特异性缺乏x- box结合蛋白1且内质网应激被剥夺的xbp(f/f) MRP8-cre小鼠，我们证实中性粒细胞内质网应激是体内颗粒释放所必需的，并导致ALI，而抑制中性粒细胞内质网应激可显著减轻ALI。综上所述，我们的研究结果表明，C5a受体介导的内质网应激诱导中性粒细胞释放颗粒，促进了ALI的发展。这一新的机制提示了ALI自噬调控的一个新的潜在治疗靶点。
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-boxbinding 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.