1. Academic Validation
  2. 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 Dis. 2020 Jun 15;11(6):459. doi: 10.1038/s41419-020-2672-0.
Feimei Zhu  # 1 Feng Xiong  # 2 Jinchen He 1 Keyun Liu 3 Yuanyuan You 1 Qian Xu 1 Junming Miao 1 Yu Du 1 Lijuan Zhang 2 Hongyu Ren 1 Xiaoying Wang 1 Junli Chen 1 Jingyu Li 1 Shanze Chen 1 Xiaokang Liu 4 Ning Huang 5 Yi Wang 6
Affiliations

Affiliations

  • 1 Department of Pathophysiology, West China College of Basic medical sciences & Forensic Medicine, Sichuan University, 610041, Chengdu, China.
  • 2 Department of Cardiology, The third People's Hospital of Chengdu, 610031, Chengdu, China.
  • 3 Department of Physiology, School of Medicine, Hubei University for Nationalities, 445000, Enshi, China.
  • 4 Department of Pharmacology, West China College of Basic medical sciences & Forensic Medicine, Sichuan University, 610041, Chengdu, China.
  • 5 Department of Pathophysiology, West China College of Basic medical sciences & Forensic Medicine, Sichuan University, 610041, Chengdu, China. huangpanxiao@sina.com.
  • 6 Department of Pathophysiology, West China College of Basic medical sciences & Forensic Medicine, Sichuan University, 610041, Chengdu, China. wangyi83@scu.edu.cn.
  • # Contributed equally.
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.

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