| First Author | Chawla M | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 25 | PubMed ID | 34155144 |
| Mgi Jnum | J:339767 | Mgi Id | MGI:6718768 |
| Doi | 10.1073/pnas.2024828118 | Citation | Chawla M, et al. (2021) An epithelial Nfkb2 pathway exacerbates intestinal inflammation by supplementing latent RelA dimers to the canonical NF-kappaB module. Proc Natl Acad Sci U S A 118(25):e2024828118 |
| abstractText | Aberrant inflammation, such as that associated with inflammatory bowel disease (IBD), is fueled by the inordinate activity of RelA/NF-kappaB factors. As such, the canonical NF-kappaB 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-kappaB pathway typically promotes immune organogenesis involving Nfkb2 gene products. Because NF-kappaB 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-kappaB dimers, leading to a hyperactive canonical RelA response in the inflamed colon. In sum, the regulation of latent NF-kappaB dimers appears to link noncanonical Nfkb2 signaling to RelA-driven inflammatory pathologies and may provide for therapeutic targets. |
