Brd4 inhibition ameliorates Pyocyanin-mediated macrophage dysfunction via transcriptional repression of reactive oxygen and nitrogen free radical pathways
Open Access
- 15 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 11 (6), 1-16
- https://doi.org/10.1038/s41419-020-2672-0
Abstract
Macrophages play critical roles in the first-line immune defense against airway infections caused byPseudomonas 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 theNOS2(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.Funding Information
- National Natural Science Foundation of China (31701098, 31860287, 81803648, 81803183)
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