Dendritic cell (DC) dysfunctions exacerbate intestinal pathologies. However, the mechanisms compromising DC-mediated immune controls remain unclear. We found that intestinal DCs from mice subjected to experimental colitis possessed heightened non-canonical NF-κB signaling, which activates the RelB:p52 heterodimer. Genetic inactivation of this pathway in DCs alleviated inflammation in colitogenic mice. Unexpectedly, RelB:p52 deficiency diminished the transcription of Axin1, a critical component of the β-catenin destruction complex. This reinforced β-catenin-driven expression of Raldh2, which imparts tolerogenic DC attributes by promoting retinoic acid (RA) synthesis. Indeed, DC-specific non-canonical NF-κB impairment improved the colonic frequency of Tregs and IgA+ B cells, which fostered luminal IgA and eubiosis. Introducing β-catenin haploinsufficiency in non-canonical NF-κB-deficient DCs moderated Raldh2 activity, reinstating colitogenic sensitivity in mice. Finally, IBD patients displayed a deleterious non-canonical NF-κB signature in intestinal DCs. In sum, we establish a DC network that integrates non-canonical NF-κB signaling to subvert RA metabolic pathway in fueling intestinal inflammation.
Link to the publication: https://www.biorxiv.org/content/10.1101/2023.12.03.569755v2.abstract