Selective Antagonists of the Bronchiolar Epithelial NF-κB-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation

• Published in: Cell reports (Cambridge) 2018-04, Vol.23 (4), p.1138-1151
• Main Authors: Tian, Bing, Liu, Zhiqing, Yang, Jun, Sun, Hong, Zhao, Yingxin, Wakamiya, Maki, Chen, Haiying, Rytting, Erik, Zhou, Jia, Brasier, Allan R.
• Format: Article
• Language: English
• Subjects: airway inflammation; Animals; bromodomain containing protein 4; Bronchi - metabolism; Bronchi - pathology; Bronchi - virology; histone acetyltransferase activity; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Inflammation - virology; innate immune response; Mice; Mice, Transgenic; NF-κB; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pneumonia, Viral - genetics; Pneumonia, Viral - metabolism; Pneumonia, Viral - pathology; Pneumonia, Viral - virology; Respiratory Mucosa - metabolism; Respiratory Mucosa - virology; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; Signal Transduction; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.03.106

The mechanisms by which the mammalian airway detects invading viral pathogens to trigger protective innate neutrophilic inflammation are incompletely understood. We observe that innate activation of nuclear factor κB (NF-κB)/RelA transcription factor indirectly activates atypical BRD4 histone acetyltransferase (HAT) activity, RNA polymerase II (Pol II) phosphorylation, and secretion of neutrophilic chemokines. To study this pathway in vivo, we developed a conditional knockout of RelA in distal airway epithelial cells; these animals have reduced mucosal BRD4/Pol II activation and neutrophilic inflammation to viral patterns. To further understand the role of BRD4 in vivo, two potent, highly selective small-molecule BRD4 inhibitors were developed. These well-tolerated inhibitors disrupt the BRD4 complex with Pol II and histones, completely blocking inducible epithelial chemokine production and neutrophilia. We conclude that RelA-BRD4 signaling in distal tracheobronchiolar epithelial cells mediates acute inflammation in response to luminal viral patterns. These potent BRD4 antagonists are versatile pharmacological tools for investigating BRD4 functions in vivo. [Display omitted] •Innate stimuli activate NF-κB/RelA and indirectly induce BRD4 HAT activity•Activity of the RelA-BRD4 complex controls neutrophil chemokine production•The RelA-BRD4 pathway in Scgb1a1-expressing cells is required for airway inflammation•Highly selective inhibitors of BRD4 reduce neutrophilic airway inflammation Tian et al. demonstrate that viral patterns activate RelA to complex with BRD4 and indirectly activate its enzymatic activity in distal trachea-bronchiolar cells to induce acute neutrophilic airway inflammation. Two highly selective, small-molecule inhibitors of BRD4 were developed. These disrupt BRD4 complex formation, HAT activity, and neutrophilia in vivo.