Abstract
Alveolar macrophages (AM) maintain airway immune balance; however, the regulation of heterogeneity of AMs is incompletely understood. We demonstrate that RGS1 coregulates the immunophenotype of AM subpopulations, including pro- and anti-inflammatory, injury- and repair-associated, and pro- and antifibrotic phenotypes, through the PLC-IP3R signal-dependent intracellular Ca2+ response. Flt3+ AMs and Tie2+ AMs had different immune properties, and RGS1 expression in the cells was targeted by exosomes (EXOs) containing miR-223 and miR-27b-3p that were derived from vascular endothelial cells (EnCs) and type II alveolar epithelial cells (EpCs-II), respectively. Imbalance of AMs was correlated with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and pulmonary fibrosis (PF) caused a lack of secretion of CD31+ and CD74+ EXOs derived from EnCs and EpCs-II. Timely treatment with EXOs significantly improved endotoxin-induced ALI/ARDS and bleomycin-induced PF in mice. Thus, EnC- and EpC-II-derived EXOs regulate the immune balance of AMs and can be used as potential therapeutic drugs.
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Acknowledgements
We thank the institutes’ platform support and all the patients who agreed for this study.
Funding
This study was supported by the National Natural Science Foundation of China (81800082, 81802651, 81172790, and 81671586) and the grants from The Recruitment Program of Overseas High-Level Young Talents, “Innovative and Entrepreneurial Team” (No.(2018)2015), Science and Technology Grant (BE2019758) and the Six Talent Peaks Project (TD-SWYY-007) of Jiangsu Province and High-Level Talents Program of Nanjing Medical University; Funding of Postdoctoral Funding of Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University, and “Peak” Training Program for Scientific Research of Yijishan Hospital, Wannan Medical College (No.GF2019G19); The Medical Interdisciplinary Research Funding of Henan University (No. CJ1205A0240011).
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ZF and HX conceived the project. ZF, JZ, and RX performed the majority of the experiments. QL, LY, XC, and YJ helped in some experiments. YL and QC provide the clinical samples. GC and MW provided the transgenic mice. YZ and YW provided critical advice to the project and funding support. ZF wrote the manuscript and HX supervised the project.
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Feng, Z., Zhou, J., Liu, Y. et al. Epithelium- and endothelium-derived exosomes regulate the alveolar macrophages by targeting RGS1 mediated calcium signaling-dependent immune response. Cell Death Differ 28, 2238–2256 (2021). https://doi.org/10.1038/s41418-021-00750-x
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DOI: https://doi.org/10.1038/s41418-021-00750-x
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