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

Abstract

Aberrant inflammation associated with human ailments, including inflammatory bowel disease (IBD), is typically fuelled by the inordinate activity of RelA/NF-κB transcription factors. As such, the canonical NF-κB 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-κB pathway promotes immune organogenesis involving Nfkb2 gene products. Because NF-κB pathways are intertwined, we asked if noncanonical signaling aggravated inflammatory RelA activity. Our investigation revealed frequent engagement of the noncanonical pathway in human IBD. In a mouse model, an Nfkb2 function exacerbated gut inflammation by amplifying the epithelial RelA activity induced upon intestinal injury. Our mechanistic studies clarified that cell-autonomous Nfkb2 signaling supplemented latent NF-κB dimers leading to hyperactive canonical RelA response in the inflamed colon. In sum, regulation of latent NF-κB dimers links noncanonical signaling to RelA-driven inflammatory pathologies and may provide for therapeutic targets.