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

The canonical NF-κB pathway mediates controlled nuclear activation of RelA factors, which induce proinflammatory genes. Uncontrolled RelA activity, however, fuels aberrant intestinal inflammation. What triggers pathological RelA activity in the colitogenic gut remains unclear. The noncanonical NF-κB module typically directs immune organogenesis involving Nfkb2 gene products. We find that this otherwise harmless noncanonical signaling amplifies canonical RelA activity in the inflamed colon in inflammatory bowel disease patients and in colitogenic mice, aggravating gut pathologies. Our work further suggests that noncanonical signaling supplements copious amounts of RelA dimers, whose activation by canonical signaling exacerbates gut inflammation. In sum, we reveal a mechanism regulating disease-associated inflammation and present the noncanonical Nfkb2 pathway as an attractive therapeutic option in inflammatory diseases.