An epithelial Nfkb2 pathway exacerbates intestinal inflammation by supplementing latent RelA dimers to the canonical NF-κB module

Aberrant inflammation, such as that associated with inflammatory bowel disease (IBD), is fueled by the inordinate activity of RelA/NF-kappa B factors. As such, the canonical NF-KB module mediates controlled nuclear activation of RelA dimers from the latent cytoplasmic complexes. What provokes pathological RelA activity in the colitogenic gut remains unclear. The noncanonical NF-kappa B pathway typically promotes immune organogenesis involving Nfkb2 gene products. Because NF-kappa B pathways are intertwined, we asked whether noncanonical signaling aggravated inflammatory RelA activity. Our investigation revealed frequent engagement of the noncanonical pathway in human IBD. In a mouse model of experimental colitis, we established that Nfkb2-mediated regulations escalated the RelA-driven proinflammatory gene response in intestinal epithelial cells, exacerbating the infiltration of inflammatory cells and colon pathologies. Our mechanistic studies clarified that cell-autonomous Nfkb2 signaling supplemented latent NF-kappa B dimers, leading to a hyperactive canonical RelA response in the inflamed colon. In sum, the regulation of latent NF-kappa B dimers appears to link noncanonical Nfkb2 signaling to RelA-driven inflammatory pathologies and may provide for therapeutic targets.

Automated summary

Research suggests that in inflammatory bowel disease (IBD), the noncanonical NF-kappa B signaling pathway is frequently involved and plays a critical role, activating the proinflammatory gene response driven by RelA and aggravating intestinal inflammation.