Noncanonical NF-κB signaling and the essential kinase NIK modulate crucial features associated with eosinophilic esophagitis pathogenesis

Abstract

Eosinophilic 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-κB-inducing 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.

Pulmonary Exposure to Magnéli Phase Titanium Suboxides Results in Significant Macrophage Abnormalities and Decreased Lung Function

“…To better define the mechanisms underlying the in vivo response to Magnéli phase exposure, lung tissue was collected 7 days post-exposure. Total RNA was isolated and processed for gene expression profiling using the SuperArray platform and IPA, as previously described (7–9). The gene expression profiling analysis revealed significant changes in several pathways associated with cell death and lung function.…”

“…Ingenuity Pathways Analysis (IPA) and the manufacturer's array software (Qiagen) was used to analyze gene expression data and conduct pathway analysis. IPA data were ranked and evaluated based on z -score as previously described by the research team (7–9).…”

From gene to treatment: supporting rare disease translational research through model systems

“…Often, a gene's downstream targets may be validated by proteomics or transcriptomics. For example, the includes an article describing a mouse model for a rare allergic disease called eosinophilic esophagitis (EoE) whose phenotype strongly models the human disease (Eden et al, 2017). Mouse gene expression datasets were compared with those of humans with EoE, and confirmed by protein studies, demonstrating target validity, and revealing a new role for non-canonical NF-κB signalling in the disorder.…”

Noncanonical NF-κB Signaling Upregulation in Inflammatory Bowel Disease Patients is Associated With Loss of Response to Anti-TNF Agents

“…The noncanonical NF-κB pathway has been recognized as a key regulator and promoter of the adaptive immune system, particularly in the development of secondary lymphoid organs. Prior studies from our group have demonstrated the role of this signaling pathway in mouse models of colon inflammation and eosinophilic esophagitis ( Allen et al, 2012 ; Eden et al, 2017 ).…”