Central role of the NF-κB pathway in the Scgb1a1-expressing epithelium in mediating respiratory syncytial virus-induced airway inflammation

Bing Tian, Jun Yang, Yingxin Zhao, Teodora Ivanciuc, Hong Sun, Maki Wakamiya, Roberto Garofalo, Allan R. Brasier

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Lower respiratory tract infection with respiratory syncytial virus (RSV) produces profound inflammation. Despite an understanding of the role of adaptive immunity in RSV infection, the identity of the major sentinel cells initially triggering inflammation is controversial. Here we evaluate the role of nonciliated secretoglobin (Scgb1a1)-expressing bronchiolar epithelial cells in RSV infection. Mice expressing a tamoxifen (TMX)-inducible Cre recombinase-estrogen receptor fusion protein (CreERTM) knocked into the Scgb1a1 locus were crossed with mice that harbor a RelA conditional allele (RelAfl), with loxP sites flanking exons 5 to 8 of the Rel homology domain. The Scgb1a1CreERTM/+ × RelAfl/fl mouse is a RelA conditional knockout (RelACKO) of a nonciliated epithelial cell population enriched in the small bronchioles. TMX-treated RelACKO mice have reduced pulmonary neutrophilic infiltration and impaired expression and secretion of NF-κB-dependent cytokines in response to RSV. In addition, RelACKO mice had reduced expression levels of interferon (IFN) regulatory factor 1/7 (IRF1/7) and retinoic acid-inducible gene I (RIG-I), components of the mucosal IFN positive-feedback loop. We demonstrate that RSV replication induces RelA to complex with bromodomain-containing protein 4 (BRD4), a cofactor required for RNA polymerase II (Pol II) phosphorylation, activating the atypical histone acetyltransferase (HAT) activity of BRD4 required for phospho-Ser2 Pol II formation, histone H3K122 acetylation, and cytokine secretion in vitro and in vivo. TMXtreated RelACKO mice have less weight loss and reduced airway obstruction/hyperreactivity yet similar levels of IFN-γ production despite higher levels of virus production. These data indicate that the nonciliated Scgb1a1-expressing epithelium is a major innate sensor for restricting RSV infection by mediating neutrophilic inflammation and chemokine and mucosal IFN production via the RelA-BRD4 pathway.

Original languageEnglish (US)
Article numbere00441-18
JournalJournal of Virology
Volume92
Issue number11
DOIs
StatePublished - Jun 1 2018

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Keywords

  • Histone acetyltransferase
  • IFN
  • Innate immunity
  • Mucosal inflammation
  • NF-κB
  • Respiratory syncytial virus
  • RSV

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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