Lack of NF‐κB‐Inducing Kinase (NIK) Results in Eosinophilic Esophagitis (EoE) and Gastric Hyperplasia in Mice: Implications for Noncanonical NF‐κB Signaling in Human EoE

The NF‐κB pathway is a powerful modulator of inflammation in the gut that can proceed along two distinct arms defined as the canonical and noncanonical pathways. The canonical pathway is well characterized and is responsible for the production of a variety of common proinflammatory mediators that contribute to gastrointestinal disease. However, the noncanonical pathway is understudied and its activation produces a distinct set of chemokines that may also be involved inflammation in the gut. NF‐κB inducing kinase (NIK) is a central molecule in noncanonical signaling and is essential for the production of downstream effector molecules. Mice lacking NIK have been previously shown to develop eosinophilic inflammation in major organs such as skin, liver, and lung. However, characterization of the gastrointestinal tract of these mice has been lacking. Here we show that Nik −/− mice display significant eosinophilic esophagitis (EoE) that has many features in common with human EoE, including intraepithelial eosinophil accumulation and degranulation, microabscess formation, fibrosis, and basal cell hyperplasia. Additionally, these mice display gastric hyperplasia most prominently at the gastroesophageal junction, suggestive of chronic irritation due to reflux. Interestingly, eosinophil infiltration is localized to the esophagus and around the gastroesophageal junction; the caudal glandular stomach, small intestines, and colons of these mice are unaffected, again similar to the human disease. Esophageal tissue of Nik −/− mice contains significantly elevated mRNA levels of thymic stromal lymphopoietin (TSLP), a gene associated with EoE, as well as major Th2 mediators IL‐4 and IL‐13. In a bioinformatics metadata analysis of gene expression from human EoE biopsy specimens, we found significant differences in gene expression associated with dysregulated noncanonical signaling that is consistent with our findings in the Nik −/− mice. Together, these findings suggest that Nik −/− mice may useful as a naturally occurring model of EoE and highlights a novel role for noncanonical NF‐κB signaling in eosinophilic gastrointestinal disease. Support or Funding Information Research reported in this work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Numbers K01DK092355 and R03DK105975. Student work on this publication was supported by the National Institute of Allergy and Infectious Diseases Animal Model Research for Veterinarians (AMRV) training grant (T32‐OD010430). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported through the VA‐MD College of Veterinary Medicine and the Institute of Critical Technology and Applied Sciences at Virginia Tech. Additional financial support for EB 2017 attendance was generously provided by a travel grant from the American Society for Investigative Pathology (ASIP) and the American College of Veterinary Pathologists (ACVP)Nik −/− mice spontaneously develop eosinophilic eosophagitis Compared to wild‐type littermates (A), Nik −/− mice display florid eosinophilic infiltration into the submucosa and mucosal epithelium of the esophagus along with basal cell hyperplasia (B, arrows), fibrosis, and eosinophilic microabscesses with degranulation (C, arrow). Many sections contain >15 eosinophils per high‐power field (D), consistent with diagnostic criteria for human EoE.