Non-canonical NF-κB signaling promotes intestinal inflammation by restraining the tolerogenic β-catenin-Raldh2 axis in dendritic cells

Abstract

AbstractDendritic 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.Significance (100)Distorted dendritic cell (DC) functions have been implicated in aberrant intestinal inflammation; however, the underlying mechanism remains obscure. We discovered that the non-canonical NF-κB pathway exacerbates inflammation in the colitogenic gut by downmodulating β-catenin-driven synthesis of Raldh2 in DCs. Raldh2 represents a key enzyme involved in the production of tolerogenic retinoic acid in intestinal DCs. Beyond regulating immune genes, therefore, non-canonical NF-κB signaling appears to instruct retinoic acid-mediated control of gut health. While we illustrate a DC network integrating immune signaling and micronutrient metabolic pathways in the intestine, our finding may have broad relevance for nutritional interventions in inflammatory ailments.eToCDeka and Kumaret al. illustrate a DC-circuitry that exacerbates intestinal inflammation in IBD patients and colitogenic mice. Non-canonical NF-κB signaling restrains β-catenin in DCs to downmodulate Raldh2, which promotes tolerogenic RA synthesis, leading to diminished Treg and IgA+cell frequencies in the gut.HighlightsAberrant intestinal inflammation is associated with and exacerbated by non-canonical NF-κB signaling in DCs.Non-canonical signaling restrains the tolerogenic β-catenin-Raldh2 axis in DCs by upregulating Axin1.DC-specific RelB:p52 impairment promotes β-catenin-dependent Treg accumulation in the gut.A DC defect of non-canonical signaling causes β-catenin-dependent increase in luminal sIgA, fostering the gut microbiome.One sentenceThe non-canonical NF-κB pathway fuels intestinal inflammation by waning the tolerogenic β-catenin-Raldh2-retinoic acid axis in DCs.