Noncanonical NF-κB signaling is suppressed through the negative regulation of the essential kinase NIK and attenuation is associated with eosinophilic esophagitis pathogenesis

Abstract

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. NF-κB signaling is a master regulator of gene transcription and drives diverse biological processes of relevance to EoE. NF-κB activation occurs through either canonical or noncanonical pathways. In general, there is a relative paucity of knowledge regarding noncanonical NF-κB regulation and signaling. Previously, we have shown that mice with hyperactive noncanonical NF-κB signaling are more susceptible to Th1/Th17 mediated experimental colitis and cancer. Conversely, mice with attenuated noncanonical NF-κB signaling spontaneously develop EoE. The objective of our current study is to translate these findings from mouse models to human patients. Clinical specimens were collected from a cohort of 16 EoE patients and representative controls. Gene expression and protein analysis revealed a significant decrease in p52, RelB, and chemokines specifically associated with noncanonical NF-κB signaling correlated with EoE. However, we also identified a significant change in several mediators that should increase noncanonical NF-κB signaling upstream of the essential kinase NIK. Thus, our data suggest a disconnect between pathway activation and p52/RelB mediated gene transcription, with NIK functioning as a key regulatory target. Further analysis identified 6 regulatory proteins that target NIK in EoE patient specimens and robustly attenuate downstream noncanonical NF-κB signaling. Together, these data demonstrate the significance of this understudied pathway in human EoE and identify potential targets for future therapeutic strategies.