Dysregulation of Noncanonical NF-κB Signaling in Gastrointestinal Diseases

Regulation of host health is intricately coordinated by a diverse interplay of immune cells detecting assaults from pathogens via recognition of pathogen associated molecular patterns (PAMPs) to mount an immune response, as well as detecting damage associated molecular patterns (DAMP) to indicate an area of damage and signal tissue repair. The gastrointestinal tract is a major signaling hub for such immune responses, as intestinal epithelial cells (IECs) compose the epithelial barrier, immune cells surveillance breached barriers to regulate the gut microbiome, and intestinal stem cells (ISCs) proliferate to replenish the IEC pool. One such method for regulating these cellular functions downstream of PAMPs/DAMPs within the gastrointestinal tract is via NF-κB signaling. This cellular signaling pathway is activated by one of two pathways: the well- defined canonical NF-κB pathway and the understudied noncanonical NF-κB pathway. The noncanonical NF-κB pathway is unique as it requires NIK, the NF-κB-inducing Kinase, to further elicit signal transduction of this pathway. Noncanonical NF-κB activation is critical to maintaining gut health, as signaling is regulated at a precise level to ensure a balance of pro-/anti-inflammatory signals to elicit a proper damage response. Any perturbations to NIK-activated signaling significantly predisposes the gastrointestinal niche towards chronic inflammatory conditions of the gastrointestinal tract.

 In this work, we explore the potential involvement of dysregulated noncanonical NF-κB signaling in inducing chronic inflammatory diseases of the gut, including Eosinophilic Esophagitis (upper GI tract), Celiac Disease/Non-Celiac Gluten Sensitivities (small intestine), Inflammatory Bowel Disease (entire intestine/large intestine), and an inflammatory subtype of colorectal cancer being Colitis-Associated Colorectal Cancer (large intestine). We study this pathway via the use of murine models bearing genetic deletions, cellular models, and the generation of miniature organs (i.e. "organoids") in petri dishes. Further, we assess varying levels of NF-κB signaling through the genetic deletions of NIK and RelA to inhibit noncanonical and canonical NF-κB pathways, respectively. Reciprocally, we also examine overactivated signaling via loss of the negative regulatory NLRs, which are proteins that function to impede NF-κB signaling. Clinical relevancy of this work is evaluated using biopsy samples collected from human patients with active disease states. Culminating our work, we find that noncanonical NF-κB signaling levels is both tissue- and cell-type specific in driving disease formation. Finally, we conclude our findings by suggesting the promise of NIK as a potential candidate for disease biomarkers and a target for future drug development.