Emerging Roles for Noncanonical NF-κB Signaling in the Modulation of Inflammatory Bowel Disease Pathobiology

Abstract

Crohn’s disease and ulcerative colitis are common and debilitating manifestations of inflammatory bowel disease (IBD). IBD is characterized by a radical imbalance in the activation of pro-inflammatory and anti-inflammatory signaling pathways in the gut. These pathways are controlled by NF-κB, which is a master regulator of gene transcription. In IBD patients, NF-κB signaling is often dysregulated resulting in overzealous inflammation. NF-κB activation occurs through two distinct pathways, defined as either canonical or non-canonical. Canonical NF-κB pathway activation is well studied in IBD and is associated with the rapid, acute production of diverse pro-inflammatory mediators, such as COX-2, IL-1β, and IL-6. In contrast to the canonical pathway, the non-canonical or “alternative” NF-κB signaling cascade is tightly regulated and is responsible for the production of highly specific chemokines that tend to be associated with less acute, chronic inflammation. There is a relative paucity of literature regarding all aspects of non-canonical NF-κB signaling. However, it is clear that this alternative signaling pathway plays a considerable role in maintaining immune system homeostasis and likely contributes significantly to the chronic inflammation underlying IBD. Non-canonical NF-κB signaling may represent a promising new direction in the search for therapeutic targets and biomarkers associated with IBD. However, significant mechanistic insight is still required to translate the current basic science findings into effective therapeutic strategies.

A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in a complex disease

“…We propose T cell specificity in Clusters 1 and 3, via NFKB1 and indirect involvement through the FC-gamma receptor pathways. This is supported by the literature: NFKB1 is involved in T-cell maturation 66 .…”

Plumericin prevents intestinal inflammation and oxidative stress in vitro and in vivo

“…Data are expressed as the mean ± SEM of 10 mice for each group. 42 Our data indicate that plumericin inhibits p65-NF-κB nuclear translocation in IEC-6, thus contributing to a significant reduction in the inflammatory cascade. 30,31 They often lead to relapsing bouts and chronic courses, and they can progress to fibrosis, often resulting in pharmacologically unmanageable alterations that need to be resolved, finally, by surgical resections.…”

Modulating inflammation through the negative regulation of NF-κB signaling

“…In general, cells from patients with mutations in TNFIAP3 show increased degradation of IκBα, p65 nuclear translocation, and subsequent expression of a range of proinflammatory cytokines associated with canonical NF-κB signaling [141]. Interestingly, the host microbiome significantly contributes to the pathogenesis of the majority of the diseases linked to A20 dysfunction and proper NF-κB signaling is a key element required to keep the balance between commensal and pathogenic microbes, especially in the gut [142]. Thus, it is possible that dysfunctional A20 regulation of NF-κB signaling could contribute to dysbiosis and disease in human patients.…”

“…Interestingly, in addition to Lys-63 mediated de-ubiquitination, CYLD has the ability to de-ubiquitinate via linear Ub chains [148]. It is interesting to note that CYLD and A20 cleave Ub chains on several of the same substrates that participate in the signal transduction cascade in the NF-κB pathway, including but not limited to RIP1, IKKγ, TRAF2 and TRAF6 [142, 145, 149, 150] ( Figure 5) . This overlap in negative regulatory function demonstrates the importance of signaling molecules, such as TRAF6, as primary nodes in the induction of the inflammatory cascade.…”

“…141 Interestingly, the host microbiome significantly contributes to the pathogenesis of the majority of the diseases linked to A20 dysfunction and proper NF-B signaling is a key element required to keep the balance between commensal and pathogenic microbes, especially in the gut. 142 Thus, it is possible that dysfunctional A20 regulation of NF-B signaling could contribute to dysbiosis and disease in human patients. Indeed, support for this hypothesis has already been reported in mouse models where spontaneous hyperinflammation in chimeric mice reconstituted with A20 −/− bone marrow were rescued using antibiotic microbiota ablation.…”