• Ting Gong, Xuedi Zhang, Xiaolei Liu, Yinfeng Ye, Zhiyuan Tian, Shuang Yin, Min Zhang, Jing Tang, and Youtan Liu.
• Department of Anesthesiology, Shenzhen Hospital of Southern Medical University, No.1333, Xinhu Road, Baoan District, Shenzhen 518110, Guangdong, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China. Electronic address: gongting2255@163.com.
• Transl Res. 2024 Aug 1; 270: 668066-80.

AbstractSepsis-induced acute lung injury (ALI) is a serious complication of sepsis and the predominant cause of death. Exosomes released by lung tissue cells critically influence the progression of ALI during sepsis by modulating the inflammatory microenvironment. However, the molecular mechanisms by which exosome-mediated intercellular signaling exacerbates ALI in septic infection remain undefined. Our study found increased levels of exosomal Tenascin-C (TNC) in the plasma of both patients and mice with ALI, showing a strong association with disease progression. By integrating exosomal proteomics with transcriptome sequencing and experimental validation, we elucidated that LPS induce unresolved endoplasmic reticulum stress (ERs) in alveolar epithelial cells (AECs), ultimately leading to the release of exosomal TNC through the activation of PERK-eIF2α and the transcription factor CHOP. In the sepsis mouse model with TNC knockout, we noted a marked reduction in macrophage pyroptosis. Our detailed investigations found that exosomal TNC binds to TLR4 on macrophages, resulting in an augmented production of ROS, subsequent mitochondrial damage, activation of the NF-κB signaling pathway, and induction of DNA damage response. These interconnected events culminate in macrophage pyroptosis, thereby amplifying the release of inflammatory cytokines. Our findings demonstrate that exosomal Tenascin-C, released from AECs under unresolved ER stress, exacerbates acute lung injury by intensifying sepsis-associated inflammatory responses. This research provides new insights into the complex cellular interactions underlying sepsis-induced ALI.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

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