Targeting BRD4 with PROTAC degrader ameliorates LPS-induced acute lung injury by inhibiting M1 alveolar macrophage polarization

Li，Difei; Deng，Yao; Wen，Guanxi; Wang，Lingwei; Shi，Xing; Chen，Shanze; Chen，Rongchang

2024-05-10

10.1016/j.intimp.2024.111991

International Immunopharmacology   影响因子和分区

1567-5769

1878-1705

Objectives: Acute lung injury (ALI) is a highly inflammatory condition with the involvement of M1 alveolar macrophages (AMs) polarization, eventually leading to the development of non-cardiogenic edema in alveolar and interstitial regions, accompanied by persistent hypoxemia. Given the significant mortality rate associated with ALI, it is imperative to investigate the underlying mechanisms of this condition so as to identify potential therapeutic targets. The therapeutic effects of the inhibition of bromodomain containing protein 4 (BRD4), an epigenetic reader, has been proven with high efficacy in ameliorating various inflammatory diseases through mediating immune cell activation. However, little is known about the therapeutic potential of BRD4 degradation in acute lung injury. Methods: This study aimed to assess the protective efficacy of ARV-825, a novel BRD4-targeted proteolysis targeting chimera (PROTAC), against ALI through histopathological examination in lung tissues and biochemical analysis in bronchoalveolar lavage fluid (BALF). Additionally, the underlying mechanism by which BRD4 regulated M1 AMs was elucidated by using CUT & Tag assay. Results: In this study, we found the upregulation of BRD4 in a lipopolysaccharide (LPS)-induced ALI model. Furthermore, we observed that intraperitoneal administration of ARV-825, significantly alleviated LPS-induced pulmonary pathological changes and inflammatory responses. These effects were accompanied by the suppression of M1 AMs. In addition, our findings revealed that the administration of ARV-825 effectively suppressed M1 AMs by inhibiting the expression of IRF7, a crucial transcriptional factor involved in M1 macrophages. Conclusion: Our study suggested that targeting BRD4 using ARV-825 is a potential therapeutic approach for ALI.

Acute lung injury Alveolar macrophage polarization ARV-825 Bromodomain-containing protein 4 CUT & Tag assay Interferon regulator factor 7

SCI

英语

第一 ; 通讯

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85189824816

Scopus

Department of Pulmonary and Critical Care Medicine,Shenzhen Institute of Respiratory Diseases,The First Affiliated Hospital (Shenzhen People's Hospital) and School of Medicine,Southern University of Science and Technology,Shenzhen,518055,China

Li，Difei,Deng，Yao,Wen，Guanxi,et al. Targeting BRD4 with PROTAC degrader ameliorates LPS-induced acute lung injury by inhibiting M1 alveolar macrophage polarization[J]. International Immunopharmacology,2024,132.

Li，Difei.,Deng，Yao.,Wen，Guanxi.,Wang，Lingwei.,Shi，Xing.,...&Chen，Rongchang.(2024).Targeting BRD4 with PROTAC degrader ameliorates LPS-induced acute lung injury by inhibiting M1 alveolar macrophage polarization.International Immunopharmacology,132.

Li，Difei,et al."Targeting BRD4 with PROTAC degrader ameliorates LPS-induced acute lung injury by inhibiting M1 alveolar macrophage polarization".International Immunopharmacology 132(2024).