Macrophage-Derived Exosomal BMPR2 Mediates Alveolar Epithelial Repair and Cellular Crosstalk in Acute Lung Injury

Xiang Yun,1– 3 Fei Li,1 Zhen Chen,4 Jiahua Meng,1 Lin Zhang,2,3,5 Juxiang Yuan1 1School of Public Health, North China University of Science and Technology, Tangshan, 063000, People’s Republic of China; 2Clinical Medical Research Center for Women and Children Diseases, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250001, People’s Republic of China; 3Key Laboratory of Occupational Exposure and Fertility Preservation for Women of Shandong Health Commission, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250001, People’s Republic of China; 4School of Public Health, Shandong second Medical University, Weifang, 261053, People’s Republic of China; 5Henan Medical Key Laboratory for Research of Trauma and Orthopedics, the Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453000, People’s Republic of ChinaCorrespondence: Juxiang Yuan, School of Public Health, North China University of Science and Technology, Tangshan, 063000, People’s Republic of China, Email [email protected] Lin Zhang, Clinical Medical Research Center for Women and Children Diseases, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250001, People’s Republic of China, Tel +86-531-68795920, Email [email protected]: Acute lung injury (ALI)/Acute respiratory distress syndrome (ARDS) continues to be a predominant cause of morbidity and mortality among critically ill patients, with few therapeutic options available. Although macrophage-derived exosomes have been identified as significant mediators of intercellular communication in tissue repair, their specific molecular mechanisms in the context of ALI remain inadequately understood. This study aims to investigate the role of macrophage-derived exosomes containing bone morphogenetic protein receptor 2 (BMPR2) in promoting the repair of blast-induced acute lung injury.Methods: We established an in vitro blast injury model utilizing MLE-12 alveolar epithelial cells and isolated exosomes from J774A.1 macrophages through ultracentrifugation. Coculture experiments were conducted to evaluate cellular repair mechanisms, while molecular docking simulations were employed to predict protein interactions. We utilized cellular thermal shift assay (CETSA) analysis, Western blotting, and immunofluorescence to characterize the effects of exosomes on epithelial cell function and signaling pathways.Results: Macrophage-derived exosomes, with a diameter of 169.7 ± 61.6 nm, significantly enhanced the viability of alveolar epithelial cells, reduced apoptosis, and promoted proliferation following blast injury. Proteomic analysis identified BMPR2 as the predominant effector protein, with an LG score of 5.182. Molecular docking studies revealed stable binding interactions between BMPR2 and BMPR1B. Functionally, exosomes facilitated the transdifferentiation of alveolar type II (AT2) cells to type I (AT1) cells through the activation of the TGF-β signaling pathway via the BMPR1B-SMAD1-ID1 axis, thereby promoting epithelial repair and regeneration.Conclusion: This study establishes that exosomal BMPR2 derived from macrophages serves as a previously unrecognized paracrine signaling mechanism facilitating cellular crosstalk during ALI repair. The BMPR2-mediated signaling pathway offers a promising therapeutic target for the treatment of ALI, paving the way for new avenues in clinical intervention.Keywords: exosomal BMPR2, alveolar epithelial, cellular crosstalk, repair, acute lung injury