Inhibition of YAP1 activity ameliorates acute lung injury through promotion of M2 macrophage polarization

• Authors: Lu Liang, Guangzhou Medical University; Wenyan Xu, Guangzhou Medical University; Ao Shen, Guangzhou Medical University; Xiaomei Fu, Guangzhou Medical University; Huiyu Cen, Guangzhou Medical University; Srian Wang, Stomatological Hospital of Guangzhou Medical University; Zhongxiao Lin, Guangzhou Medical University; Lingmin Zhang, Guangzhou Medical University; Fangyu Lin, Emory Eye Center; Xin Zhang, State Key Laboratory of Quality Research in Chinese Medicine; Na Zhou, State Key Laboratory of Quality Research in Chinese Medicine; Jishuo Chang, Guangzhou Medical University; Zhe-Sheng Chen, St. John's University; Chuwen Li, Guangzhou Medical University; Xiyong Yu, Guangzhou Medical University
• Journal Title: MedComm
• Volume: Volume 4, Number 3
• Publisher: John Wiley & Sons, Inc | 2023-06-01, Pages e293-e293
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1002/mco2.293
• Subjects: Health Sciences, Pharmacology
• Keywords: Yes‐associated protein 1; acute lung injury; macrophage polarization; pulmonary inflammation

Abstract

The balance of M1/M2 macrophage polarization plays an important role in regulating inflammation during acute lung injury (ALI). Yes-associated protein (YAP1) is a key protein in the Hippo–YAP1 signaling pathway and is involved in macrophage polarization. We aimed to determine the role of YAP1 in pulmonary inflammation following ALI and regulation of M1/M2 polarization. Pulmonary inflammation and injury with upregulation of YAP1 were observed in lipopolysaccharide (LPS)-induced ALI. The YAP1 inhibitor, verteporfin, attenuated pulmonary inflammation and improved lung function in ALI mice. Moreover, verteporfin promoted M2 polarization and inhibited M1 polarization in the lung tissues of ALI mice and LPS-treated bone marrow-derived macrophages (BMMs). Additionally, siRNA knockdown confirmed that silencing Yap1 decreased chemokine ligand 2 (CCL2) expression and promoted M2 polarization, whereas silencing large tumor suppressor 1 (Lats1) increased CCL2 expression and induced M1 polarization in LPS-treated BMMs. To investigate the role of inflammatory macrophages in ALI mice, we performed single-cell RNA sequencing of macrophages isolated from the lungs. Thus, verteporfin could activate the immune-inflammatory response, promote the potential of M2 macrophages, and alleviate LPS-induced ALI. Our results reveal a novel mechanism where YAP1-mediated M2 polarization alleviates ALI. Therefore, inhibition of YAP1 may be a target for the treatment of ALI.