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  • Brd4 inhibition ameliorates Pyocyanin-mediated macrophage dysfunction via transcriptional repression of reactive oxygen and nitrogen free radical pathways.

Brd4 inhibition ameliorates Pyocyanin-mediated macrophage dysfunction via transcriptional repression of reactive oxygen and nitrogen free radical pathways.

Cell death & disease (2020-06-17)
Feimei Zhu, Feng Xiong, Jinchen He, Keyun Liu, Yuanyuan You, Qian Xu, Junming Miao, Yu Du, Lijuan Zhang, Hongyu Ren, Xiaoying Wang, Junli Chen, Jingyu Li, Shanze Chen, Xiaokang Liu, Ning Huang, Yi Wang
ABSTRACT

Macrophages play critical roles in the first-line immune defense against airway infections caused by Pseudomonas aeruginosa (PA). The redox-active phenazine-pyocyanin (PCN), as one of the most essential virulence factors, facilities PA-related infection via a wide spectrum of cellular oxidative damages. However, little is known for PCN cytotoxicity in macrophages. In this study, besides showing PCN-mediated reactive oxygen species (ROS) indeed involved in macrophage viability and function impairment, we at the first time demonstrated a novel role of reactive nitrogen species (RNS) pathway causing cellular damage in PCN-challenged macrophages. Using small molecule inhibitor JQ1 targeting Bromodomain and extra-terminal family proteins, we showed restrained iNOS-dependent nitric oxide (NO) production correlated with abolished Brd4 recruitment to the NOS2 (encoding inducible nitric oxide synthase-iNOS) promoter. Application of JQ1 diminished PCN-mediated peroxynitrite (ONOO-) that followed ROS and NO induction, restored macrophage survival and bacteria clearance as well as repressed local inflammation in PA/PCN-challenged mice lungs. Our results uncover a novel link between PCN-mediated macrophage dysfunction and reactive free radicals that rely on Brd4-dependent transcription modulation of multiple stress-response genes, suggesting Brd4 could be a promising therapeutic target in treating PA-related lung infection.

MATERIALS
Product Number
Brand
Product Description

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