Journal
CELL REPORTS
Volume 23, Issue 4, Pages 1138-1151Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.03.106
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Funding
- NIH [NIAID AI062885, UL1TR001439, NIEHS ES006676]
- NSF [DMS-1361411/DMS-1361318]
- UTMB Technology Commercialization Program
- Sanofi Innovation Awards (iAwards)
- Division Of Mathematical Sciences
- Direct For Mathematical & Physical Scien [1361411] Funding Source: National Science Foundation
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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 KB (NF-kappa B)/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 ReIA 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 ReIA-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.
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