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

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 p...

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Autores principales:	Kelsey Nicole Wiles, Cara Maria Alioto, Nathan Bruce Hodge, Margarette Helen Clevenger, Lia Elyse Tsikretsis, Frederick T.J. Lin, Marie-Pier Tétreault
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Gene Regulation Inflammation Immune Regulation Transcription Factor Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/86fd6ee8596c44899401516831b51150
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spelling	oai:doaj.org-article:86fd6ee8596c44899401516831b511502021-11-12T04:39:02ZIκB Kinase-β Regulates Neutrophil Recruitment Through Activation of STAT3 Signaling in the EsophagusSummary2352-345X10.1016/j.jcmgh.2021.07.007https://doaj.org/article/86fd6ee8596c44899401516831b511502021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001521https://doaj.org/toc/2352-345XBackground & 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.Kelsey Nicole WilesCara Maria AliotoNathan Bruce HodgeMargarette Helen ClevengerLia Elyse TsikretsisFrederick T.J. LinMarie-Pier TétreaultElsevierarticleGene RegulationInflammationImmune RegulationTranscription FactorDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 5, Pp 1743-1759 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Gene Regulation Inflammation Immune Regulation Transcription Factor Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Gene Regulation Inflammation Immune Regulation Transcription Factor Diseases of the digestive system. Gastroenterology RC799-869 Kelsey Nicole Wiles Cara Maria Alioto Nathan Bruce Hodge Margarette Helen Clevenger Lia Elyse Tsikretsis Frederick T.J. Lin Marie-Pier Tétreault IκB Kinase-β Regulates Neutrophil Recruitment Through Activation of STAT3 Signaling in the EsophagusSummary
description	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.
format	article
author	Kelsey Nicole Wiles Cara Maria Alioto Nathan Bruce Hodge Margarette Helen Clevenger Lia Elyse Tsikretsis Frederick T.J. Lin Marie-Pier Tétreault
author_facet	Kelsey Nicole Wiles Cara Maria Alioto Nathan Bruce Hodge Margarette Helen Clevenger Lia Elyse Tsikretsis Frederick T.J. Lin Marie-Pier Tétreault
author_sort	Kelsey Nicole Wiles
title	IκB Kinase-β Regulates Neutrophil Recruitment Through Activation of STAT3 Signaling in the EsophagusSummary
title_short	IκB Kinase-β Regulates Neutrophil Recruitment Through Activation of STAT3 Signaling in the EsophagusSummary
title_full	IκB Kinase-β Regulates Neutrophil Recruitment Through Activation of STAT3 Signaling in the EsophagusSummary
title_fullStr	IκB Kinase-β Regulates Neutrophil Recruitment Through Activation of STAT3 Signaling in the EsophagusSummary
title_full_unstemmed	IκB Kinase-β Regulates Neutrophil Recruitment Through Activation of STAT3 Signaling in the EsophagusSummary
title_sort	iκb kinase-β regulates neutrophil recruitment through activation of stat3 signaling in the esophagussummary
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/86fd6ee8596c44899401516831b51150
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IκB Kinase-β Regulates Neutrophil Recruitment Through Activation of STAT3 Signaling in the EsophagusSummary

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