Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages
Year: 2023
Type: article
Abstract: 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 Ca 2+ 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.
Source: Theranostics
DOI: 10.7150/thno.82552
Institutions: Wannan Medical College, Agency for Science, Technology and Research, National University of Singapore, Zhongda Hospital Southeast University, First Affiliated Hospital of Wannan Medical College, Anhui Normal University, Institute of Molecular and Cell Biology, Southeast University, Nanjing Medical University, Jiaxing University, Central South University, Second Xiangya Hospital of Central South University, Xiangya Hospital Central South University, Jiangsu Cancer Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,671
Funders: Beijing Xisike Clinical Oncology Research Foundation, National University of Singapore, National Natural Science Foundation of China, Government of Jiangsu Province, Southeast University, Wannan Medical College, Medical Research Council, National Medical Research Council, Jiangsu Cancer Hospital
OpenAlex ID: W4318831745