Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages

作者：Zunyong Feng, Jing Zhou, Qiang Li, Liuxi Chu, Yuxin Jiang, Xuanbo Zhang, Liang Yan, Yinhua Liu, Jing Jiang, Ping Xu, Qun Chen, Ming Wang, Hui Yang, Guoren Zhou, Xiaochun Jiang, Xiaoyuan Chen, Hongping Xia · 发表于：Theranostics · 年份：2023 · DOI：10.7150/thno.82552 · 被引用次数：48 · 研究领域：Extracellular vesicles in disease、Inflammasome and immune disorders、Phagocytosis and Immune Regulation

Background: Complete abolition of alveolar epithelial cells (AECs) is characteristic of end-stage lung disease. Transplantation therapy of type II AECs (AEC-IIs) or AEC-IIs-derived exosomes (ADEs) have been proposed as a means of repairing injury and preventing fibrosis. However, the mechanism by which ADEs balances airway immunity and alleviates damage and fibrosis remains unknown. Methods: We investigated STIM-activating enhancer-positive ADEs (STIMATE + ADEs) in the lung of 112 ALI/ARDS and 44 IPF patients, and observed the correlation between STIMATE + ADEs and subpopulation proportion and metabolic status of tissue-resident alveolar macrophages (TRAMs). We constructed the conditional knockout mice STIMATE sftpc , in which STIMATE was specifically knocked out in mouse AEC-IIs and observed the effects of STIMATE + ADEs deficiency on disease progression, immune selection and metabolic switching of TRAMs. We constructed a BLM-induced AEC-IIs injury model to observe the salvage treatment of damage/fibrosis progression with STIMATE + ADEs supplementation. Results: In clinical analysis, the distinct metabolic phenotypes of AMs in ALI/ARFS and IPF were significantly perturbed by STIMATE + ADEs. The immune and metabolic status of TRAMs in the lungs of STIMATE sftpc mice was imbalanced, resulting in spontaneous inflammatory injury and respiratory disorders. STIMATE + ADEs are taken up by tissue-resident alveolar macrophages TRAMs to regulate high Ca 2+ responsiveness and long-term...