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-{kappa}B transcription factors. As such, the canonical NF-{kappa}B 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 promotes immune organogenesis involving Nfkb2 gene products. Because NF-{kappa}B 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-{kappa}B dimers leading to hyperactive canonical RelA response in the inflamed colon. In sum, regulation of latent NF-{kappa}B dimers links noncanonical signaling to RelA-driven inflammatory pathologies and may provide for therapeutic targets. In briefNoncanonical NF-{kappa}B signals in intestinal epithelial cells supplement latent RelA dimers that, in turn, aggravated canonical NF-{kappa}B response in the colitogenic gut exacerbating intestinal inflammation. HighlightsO_LIHuman IBD involves the frequent engagement of the noncanonical NF-{kappa}B pathway. C_LIO_LIMice deficient in the noncanonical signal transducer Nfkb2 are resistant to experimental colitis. C_LIO_LINoncanonical NF-{kappa}B signaling supplements latent RelA NF-{kappa}B dimers. C_LIO_LINoncanonical NF-{kappa}B signaling amplifies canonical NF-{kappa}B response to TLR ligands. C_LI