Non-canonical NF-kB signaling limits the tolerogenic b-catenin-Raldh2 axis in gut dendritic cells
Distorted dendritic cell (DC) functions provoke aberrant intestinal inflammation; however, the underlying mechanism remains obscure. The non-canonical NF-kB pathway activates the RelB:p52 heterodimer, which is known to control immune gene expressions in DCs. We found that intestinal DCs from IBD patients possessed heightened non-canonical NF-kB signaling and that genetic inactivation of RelB:p52 in DCs instead alleviated experimental colitis in mice. Our mechanistic studies discovered that RelB:p52 deficiency led to reduced transcription of Axin1, a critical component of the b-catenin destruction complex, reinforcing a tolerogenic b-catenin-Raldh2-retinoic acid axis in DCs. Indeed, DC-specific non-canonical NF-kB impairment in mice improved the colonic frequency of Tregs and IgA+ cells, which fostered luminal IgA and the gut microbiome. Remarkably, introducing b-catenin haploinsufficiency in non-canonical NF-kB-deficient DCs reduced Raldh2 levels, reinstating the colitogenic sensitivity in mice. In sum, we elucidate that non-canonical NF-kB signaling in DCs exacerbates intestinal inflammation by waning the vitamin A metabolism pathway.