IκB Kinase-β Regulates Neutrophil Recruitment Through Activation of STAT3 Signaling in the Esophagus

Kelsey Nicole Wiles, Cara Maria Alioto*, Nathan Bruce Hodge, Margarette Helen Clevenger, Lia Elyse Tsikretsis, Frederick T.J. Lin, Marie Pier Tétreault

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background & Aims: The epithelial barrier is the host's first line of defense against damage to the underlying tissue. Upon injury, the epithelium plays a critical role in inflammation. The IκB kinase β (IKKβ)/nuclear factor-κB pathway was shown to be active in the esophageal epithelium of patients with esophageal disease. However, the complex mechanisms by which IKKβ signaling regulates esophageal disease pathogenesis remain unknown. Our prior work has shown that expression of a constitutively active form of IKKβ specifically in esophageal epithelia of mice (IkkβcaEsophageal Epithelial Cell-Knockin (EEC-KI)) is sufficient to cause esophagitis. Methods: We generated ED-L2/Cre;Rosa26-Ikkβca+/L;Stat3L/L (IkkβcaEEC-KI;Stat3Esophageal Epithelial Cell Knockout (EEC-KO)) mice, in which the ED-L2 promoter activates Cre recombinase in the esophageal epithelium, leading to constitutive activation of IKKβ and loss of Stat3. Esophageal epithelial tissues were collected and analyzed by immunostaining, RNA sequencing, quantitative real-time polymerase chain reaction assays, flow cytometry, and Western blot. IkkβcaEEC-KI mice were treated with neutralizing antibodies against interleukin (IL)23p19 and IL12p40. Results: Here, we report that IkkβcaEEC-KI mice have increased activation of epithelial Janus kinase 2/STAT3 signaling. Stat3 deletion in IkkβcaEEC-KI mice attenuated the neutrophil infiltration observed in IkkβcaEEC-KI mice and resulted in decreased expression of genes related to immune cell recruitment and activity. Blocking experiments in IkkβcaEEC-KI mice showed that STAT3 activation and subsequent neutrophil recruitment are dependent on IL23 secretion. Conclusions: Our study establishes a novel interplay between IKKβ and STAT3 signaling in epithelial cells of the esophagus, where IKKβ/IL23/STAT3 signaling controls neutrophil recruitment during the onset of inflammation. GEO accession number: GSE154129.

Original languageEnglish (US)
Pages (from-to)1743-1759
Number of pages17
JournalCMGH
Volume12
Issue number5
DOIs
StatePublished - Jan 2021

Keywords

  • Gene Regulation
  • Immune Regulation
  • Inflammation
  • Transcription Factor

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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