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bioRxiv · 10.1101/2023.12.03.569755

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

Deka, A.·Kumar, N.·Chawla, M.·Bhattacharya, N.·Ali, A. S.·Basu, S.·Bhawna,·Madan, U.·Kumar, S.·Das, B.·Sengupta, D.·Awasthi, A.·Basak, S.
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Abstract

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-{kappa}B 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 {beta}-catenin destruction complex. This reinforced {beta}-catenin-driven expression of Raldh2, which imparts tolerogenic DC attributes by promoting retinoic acid (RA) synthesis. Indeed, DC-specific non-canonical NF-{kappa}B impairment improved the colonic frequency of Tregs and IgA+ B cells, which fostered luminal IgA and eubiosis. Introducing {beta}-catenin haploinsufficiency in non-canonical NF-{kappa}B-deficient DCs moderated Raldh2 activity, reinstating colitogenic sensitivity in mice. Finally, IBD patients displayed a deleterious non-canonical NF-{kappa}B signature in intestinal DCs. In sum, we establish a DC network that integrates non-canonical NF-{kappa}B 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-{kappa}B pathway exacerbates inflammation in the colitogenic gut by downmodulating {beta}-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-{kappa}B 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 Kumar et al. illustrate a DC-circuitry that exacerbates intestinal inflammation in IBD patients and colitogenic mice. Non-canonical NF-{kappa}B signaling restrains {beta}-catenin in DCs to downmodulate Raldh2, which promotes tolerogenic RA synthesis, leading to diminished Treg and IgA+ cell frequencies in the gut. HighlightsO_LIAberrant intestinal inflammation is associated with and exacerbated by non-canonical NF-{kappa}B signaling in DCs. C_LIO_LINon-canonical signaling restrains the tolerogenic {beta}-catenin-Raldh2 axis in DCs by upregulating Axin1. C_LIO_LIDC-specific RelB:p52 impairment promotes {beta}-catenin-dependent Treg accumulation in the gut. C_LIO_LIA DC defect of non-canonical signaling causes {beta}-catenin-dependent increase in luminal sIgA, fostering the gut microbiome. C_LI One sentenceThe non-canonical NF-{kappa}B pathway fuels intestinal inflammation by waning the tolerogenic {beta}-catenin-Raldh2-retinoic acid axis in DCs.

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Deka, A., Kumar, N., Chawla, M., Bhattacharya, N., Ali, A. S., Basu, S., Bhawna,, Madan, U., Kumar, S., Das, B., Sengupta, D., Awasthi, A., Basak, S.. 2023-12-05. Non-canonical NF-κB signaling in dendritic cells promotes intestinal inflammation by restraining the tolerogenic β-catenin-Raldh2 axis. https://doi.org/10.1101/2023.12.03.569755

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