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dc.contributor.authorEden, Kristinen
dc.contributor.authorRothschild, Daniel E.en
dc.contributor.authorMcDaniel, Dylan K.en
dc.contributor.authorHeid, Bettinaen
dc.contributor.authorAllen, Irving C.en
dc.description.abstractEosinophilic esophagitis (EoE) is an allergic disease of the esophagus driven by T cell and eosinophil responses to dietary allergens, resulting in chronic mucosal inflammation. Few spontaneous animal models of esophageal eosinophilia exist, with most studies relying on artificial sensitization procedures. NF-κBinducing kinase (NIK; MAP3K14) is a key signaling molecule of the noncanonical NF-κB (NFKB1) pathway, an alternative signaling cascade producing chemokines involved in lymphoid stroma development and leukocyte trafficking. Nik−/− mice have been shown to develop a hypereosinophilic syndrome in peripheral blood and major filtering organs; however, the gastrointestinal mucosa of these mice has not been well characterized. We show that Nik−/− mice develop significant, localized eosinophilic esophagitis that mimics human EoE, including features such as severe eosinophil accumulation, degranulation, mucosal thickening, fibrosis and basal cell hyperplasia. The remainder of the GI tract, including the caudal stomach, small intestine and colon, in mice with active EoE are unaffected, also similar to human patients. Gene expression patterns in esophageal tissue of Nik−/− mice mimics human EoE, with thymic stromal lymphopoetin (TSLP) in particular also elevated at the protein level. In gene expression data sets from human biopsy specimens, we further show that many genes associated with noncanonical NF- κB signaling are significantly dysregulated in EoE patients, most notably a paradoxical upregulation of NIK itself with concurrent upregulation of powerful protein-level destabilizers of NIK. These findings suggest that Nik−/− mice could be useful as a spontaneous model of specific features of EoE and highlight a novel role for noncanonical NF-κB signaling in human patients.en
dc.description.sponsorshipNational Institutes of Healthen
dc.description.sponsorshipNIH: K01 DK092355en
dc.description.sponsorshipNIH: R03 DK105975en
dc.description.sponsorshipNIH: T32-OD010430-06en
dc.description.sponsorshipVirginia Maryland College of Veterinary Medicineen
dc.description.sponsorshipInstitute for Critical Technologies and Applied Scienceen
dc.publisherThe Company of Biologistsen
dc.rightsCreative Commons Attribution 3.0 Unporteden
dc.subjectNF-κB-inducing kinaseen
dc.titleNoncanonical NF-κB signaling and the essential kinase NIK modulate crucial features associated with eosinophilic esophagitis pathogenesisen
dc.typeArticle - Refereeden
dc.title.serialDisease Models and Mechanismsen

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Creative Commons Attribution 3.0 Unported
License: Creative Commons Attribution 3.0 Unported