An epithelialNfkb2pathway exacerbates intestinal inflammation by supplementing latent RelA dimers to the canonical NF-κB module

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. In brief Noncanonical NF-κB signals in intestinal epithelial cells supplement latent RelA dimers that, in turn, aggravated canonical NF-κB response in the colitogenic gut exacerbating intestinal inflammation. Highlights Human IBD involves the frequent engagement of the noncanonical NF-κB pathway. Mice deficient in the noncanonical signal transducer Nfkb2 are resistant to experimental colitis. Noncanonical NF-κB signaling supplements latent RelA NF-κB dimers. Noncanonical NF-κB signaling amplifies canonical NF-κB response to TLR ligands.