Sustained induction of IP-10 by MRP8/14 via the IFNβ-IRF7 axis in macrophages exaggerates lung injury in endotoxemic mice  

作　　者：Juan Wang Guiming Chen Lei Li Sidan Luo Bingrong Hu Jia Xu Haihua Luo Shan Li Yong Jiang 

机构地区：[1]Guangdong Provincial Key Laboratory of Proteomics,State Key Laboratory of Organ Failure Research,Department of Pathophysiology,School of Basic Medical Sciences,Southern Medical University,Guangzhou 510515,Guangdong,China

出　　处：《Burns & Trauma》2023年第1期273-288,共16页烧伤与创伤（英文）

基　　金：supported by grants from the National Natural Science Foundation of China(82130063,81971895 and 81501691);Special Support Plan for Outstanding Talents of Guangdong Province(2019JC05Y340).

摘　　要：Background:As a damage-associated molecular pattern,the myeloid-related protein 8/14(MRP8/14)heterodimer mediates various inflammatory diseases,such as sepsis.However,how MRP8/14 promotes lung injury by regulating the inflammatory response during endotoxemia remains largely unknown.This study aims at illuminating the pathological functions of MRP8/14 in endotoxemia.Methods:An endotoxemic model was prepared with wild-type and myeloid cell-specific Mrp8 deletion(Mrp8MC)mice for evaluating plasma cytokine levels.Lung injury was evaluated by hematoxylin and eosin(H&E)staining,injury scoring and wet-to-dry weight(W/D)ratio.The dynamic profile of interferonγ(IFNγ)-inducible protein 10(IP-10)mRNA expression induced by macrophage MRP8/14 was determined by quantitative real-time polymerase chain reaction(qPCR).Immunoblotting was used to evaluate the increase in IP-10 level induced by activation of the JAK-STAT signaling pathway.Luciferase reporter assay was performed to detect the involvement of IRF7 in Ip-10 gene transcription.In vivo air pouch experiments were performed to determine the biological function of IP-10 induced by MRP8/14.Results:Experiments with Mrp8MC mice showed that MRP8/14 promoted the production of cytokines,including IP-10,in the bronchoalveolar lavage fluid(BALF)and lung injury in endotoxic mice.The result of qPCR showed sustained expression of Ip-10 mRNA in macrophages after treatment with MRP8/14 for 12 h.Neutralization experiments showed that the MRP8/14-induced Ip-10 expression in RAW264.7 cells was mediated by extracellular IFNβ.Western blotting with phosphorylation-specific antibodies showed that the JAK1/TYK2-STAT1 signaling pathway was activated in MRP8/14-treated RAW264.7 cells,leading to the upregulation of Ip-10 gene expression.IRF7 was further identified as a downstream regulator of the JAK-STAT pathway that mediated Ip-10 gene expression in macrophages treated with MRP8/14.In vivo air pouch experiments confirmed that the IFNβ-JAK1/TYK2-STAT1-IRF7 pathway was required for chemokine(C-

关 键 词：ENDOTOXEMIA Interferon-inducible protein 10 Interferon beta Macrophage Myeloid-related protein 8/14 Interferon regulatory factor-7 

分 类 号：R363[医药卫生—病理学]