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

• Published in: Theranostics 2023-01, Vol.13 (3), p.991-1009
• Main Authors: Feng, Zunyong, Jing, Zhou, Li, Qiang, Chu, Liuxi, Jiang, YuXin, Zhang, Xuanbo, Yan, Liang, Liu, Yinhua, Jiang, Jing, Xu, Ping, Chen, Qun, Wang, Ming, Yang, Hui, Zhou, Guoren, Jiang, Xiaochun, Chen, Xiaoyuan, Xia, Hongping
• Format: Article
• Language: English
• Subjects: Alveolar Epithelial Cells - metabolism; Animals; DNA, Mitochondrial - metabolism; Fibrosis; Lung - pathology; Macrophages, Alveolar - metabolism; Mice; Mice, Knockout; Research Paper
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.82552

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. 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 , 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. 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 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 responsiveness and long-term Ca signal transduction, which maintains M2-like immunophenotype and metabolism selection. This involves calcineurin (CaN)-PGC-1α pathway mediated mitochondrial biogenesis and mtDNA coding. In a bleomycin-induced mouse fibrosis model, supplementation with inhaled STIMATE ADEs lessened early acute injury, prevented advanced fibrosis, alleviated ventilatory impairment and reduced mortality.