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

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.

Exosomal miR‑301a‑3p of airway epithelial cells regulates macrophage polarization and promotes lung injury via the GATA1 pathway in acute respiratory distress syndrome

“…However, cross-talk between airway epithelial cells and alveolar macrophages mediated by exosomal miRNAs in ARDS has rarely been reported. A recent study indicated that exosomal STIMATE, derived from type II alveolar epithelial cells, regulates the subpopulation proportion and metabolic reprogramming of macrophages in patients with ARDS and pulmonary brosis [20]. In our study, miR-301a-3p, screened using GeneChip from the GSE database, served as a potential regulator of macrophage polarization and immune responses in ARDS.…”

Extracellular vesicles derived from M2‐like macrophages alleviate acute lung injury in a miR‐709‐mediated manner

“…We have successfully associated specific experimental findings with clinical relevance, as a correlation was discovered between the components responsible for the anti-inflammatory effect of M2φ-EVs and the disease severity in ARDS patients (Figure 10). In recent years, the pivotal role of alveolar macrophage polarisation in controlling inflammatory lung diseases has gained recognition (Feng et al, 2023;Song et al, 2019). Therefore, numerous studies have focused on modulating the polarisation of macrophages, particularly with the goal of increasing the proportion of M2-like alveolar macrophages to manage ALI/ARDS (Feng et al, 2023;Song et al, 2019).…”

“…M1φ are primarily involved in proinflammatory processes, and are a major source of numerous cytokines including IL‐6, TNF‐α and IL‐1β, which contribute to tissue damage following infections (Wang et al., 2020 ). In contrast, M2φ have been shown to play anti‐inflammatory and tissue repair roles in mouse models of acute liver failure, acute kidney injury, colitis and ALI (Bai et al., 2021 ; Feng et al., 2023 ; Lin et al., 2014 ; Song et al., 2019 ; Tang et al., 2020 ), partly by inhibiting NLRP3 inflammasome activation (Bai et al., 2017 ; Bai et al., 2018 ; Bai et al., 2019 ). However, practical applications of macrophage‐oriented cell therapy in vivo face several limitations.…”

Exosomes: efficient macrophage-related immunomodulators in chronic lung diseases

“…Exosomes derived from STIM-activating enhancer-positive type II alveolar epithelial cells (AEC II) regulate high Ca2+ responsiveness and long-term Ca2+ signaling, thereby maintaining an M2-like immune phenotype and metabolic selection. This modulation helps attenuate early acute injury and helps prevent late-stage fibrosis ( Feng et al, 2023 ). Additionally, macrophages can be classified based on Ly6C into Ly6Clow, Ly6Chi, and Ly6C- macrophages.…”