Description
Dendritic cell (DC) dysfunctions exacerbate intestinal inflammation; however, the underlying mechanism remains unclear. The non-canonical NF-κB pathway activates the RelB: p52 heterodimer, which plays immunoregulatory roles in DCs. Curiously, genetic studies have associated this pathway with inflammatory bowel disease (IBD). We found that intestinal DCs from IBD patients possessed heightened non-canonical NF-κB signaling and that genetic inactivation of RelB: p52 in DCs alleviated experimental colitis in mice. Unexpectedly, RelB: p52 deficiency diminished transcription of Axin1, a critical component of the β-catenin destruction complex, thereby reinforcing the tolerogenic β-catenin-Raldh2-retinoic acid axis in DCs. Indeed, DC-specific non-canonical NF-κB impairment in mice improved the colonic frequency of Tregs and IgA+ B cells, which fostered luminal IgA and the gut microbiome. Introducing β-catenin haploinsufficiency in non-canonical NF-κB-deficient DCs moderated this tolerogenic mechanism, reinstating the colitogenic sensitivity in mice. In sum, we illustrate a DC network that integrates immune signaling and micronutrient metabolic pathways to tune intestinal inflammation.
Link to the publication: https://europepmc.org/article/ppr/ppr768836