title: Endoplasmic Reticulum Stress of Neutrophils Is Required for Ischemia/Reperfusion-Induced Acute Lung Injury.
abstract: 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.
authors.affiliation: Department of Anesthesiology, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China;
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Anesthesiology, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China;
authors.forename: Zhi-Feng
authors.initials: ZF
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China;
authors.forename: Jia
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Anesthesiology, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China;
authors.forename: Qi-Fang
authors.initials: QF
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China;
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China;
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Institute of Intervention Vessel, Tongji University, Shanghai 200092, China; and Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China zxpsibs@163.com drjianghongjy@163.com.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China; zxpsibs@163.com drjianghongjy@163.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D015936:Complement C5a / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000276:immunology*; D004722:Endoribonucleases / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: D015936:Complement C5a; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases