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

Abstract

<b>Background:</b> 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. <b>Methods:</b> 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 <i>^sftpc</i> , 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. <b>Results:</b> 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 <i>^sftpc</i> 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 Ca²⁺ responsiveness and long-term Ca²⁺ 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.