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 ß (IKKß)/nuclear factor-κB pathway was shown to be active in the esophageal epithelium of patients with esophageal disease. However, the complex mechanisms by which IKKß signaling regulates esophageal disease pathogenesis remain unknown. Our prior work has shown that expression of a constitutively active form of IKKß specifically in esophageal epithelia of mice (IkkßcaEsophageal Epithelial Cell-Knockin (EEC-KI)) is sufficient to cause esophagitis. METHODS: We generated ED-L2/Cre;Rosa26-Ikkßca+/L;Stat3L/L (IkkßcaEEC-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 IKKß 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. IkkßcaEEC-KI mice were treated with neutralizing antibodies against interleukin (IL)23p19 and IL12p40. RESULTS: Here, we report that IkkßcaEEC-KI mice have increased activation of epithelial Janus kinase 2/STAT3 signaling. Stat3 deletion in IkkßcaEEC-KI mice attenuated the neutrophil infiltration observed in IkkßcaEEC-KI mice and resulted in decreased expression of genes related to immune cell recruitment and activity. Blocking experiments in IkkßcaEEC-KI mice showed that STAT3 activation and subsequent neutrophil recruitment are dependent on IL23 secretion. CONCLUSIONS: Our study establishes a novel interplay between IKKß and STAT3 signaling in epithelial cells of the esophagus, where IKKß/IL23/STAT3 signaling controls neutrophil recruitment during the onset of inflammation. GEO accession number: GSE154129.
