OBJECTIVE: In this study, we aimed to investigate the role of the TNFSF12-TNFRSF12A pathway in mediating communication between alveolar macrophages and fibroblasts, and its implications for the development of pulmonary fibrosis in severe COVID-19 patients.
METHODS: We conducted single-cell RNA sequencing (scRNA-seq) analysis using lung tissue samples from severe COVID-19 patients and healthy controls. The data was processed, analyzed, and cell types were annotated. We focused on the communication between alveolar macrophages and fibroblasts and identified key signaling pathways. In vitro experiments were performed to validate our findings, including the impact of TNFRSF12A silencing on fibrosis reversal.
RESULTS: Our analysis revealed that in severe COVID-19 patients, alveolar macrophages communicate with fibroblasts primarily through the TNFSF12-TNFRSF12A pathway. This communication pathway promotes fibroblast proliferation and expression of fibrotic factors. Importantly, silencing TNFRSF12A effectively reversed the pro-proliferative and pro-fibrotic effects of alveolar macrophages.
CONCLUSIONS: The TNFSF12-TNFRSF12A pathway plays a central role in alveolar macrophage-fibroblast communication and contributes to pulmonary fibrosis in severe COVID-19 patients. Silencing TNFRSF12A represents a potential therapeutic strategy for mitigating fibrosis in severe COVID-19 lung disease.
目的:在本研究中,我们旨在研究TNFSF12-TNFRSF12A通路在介导肺泡巨噬细胞和成纤维细胞之间的通讯中的作用,及其对严重COVID-19患者肺纤维化发展的影响。
方法:我们使用来自严重COVID-19患者和健康对照的肺组织样本进行了单细胞RNA测序(scRNA-seq)分析。数据经过处理,分析,并对细胞类型进行了注释。我们专注于肺泡巨噬细胞和成纤维细胞之间的通讯,并确定了关键的信号通路。进行了体外实验以验证我们的发现,包括TNFRSF12A沉默对纤维化逆转的影响。
结果:我们的分析显示,在重症COVID-19患者中,肺泡巨噬细胞主要通过TNFSF12-TNFRSF12A途径与成纤维细胞交流。该通讯通路促进成纤维细胞增殖和纤维化因子的表达。重要的是,沉默TNFRSF12A可有效逆转肺泡巨噬细胞的促增殖和促纤维化作用.
结论:在重症COVID-19患者中,TNFSF12-TNFRSF12A通路在肺泡巨噬细胞-成纤维细胞通讯中起重要作用,并有助于肺纤维化。沉默TNFRSF12A代表了减轻严重COVID-19肺病纤维化的潜在治疗策略。