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

  1. Alvina Deka
  2. Naveen Kumar
  3. Meenakshi Chawla
  4. Namrata Bhattacharya
  5. Sk Asif Ali
  6. Swapnava Basu
  7. Bhawna
  8. Upasna Madan
  9. Shakti Kumar
  10. Bhabatosh Das
  11. Debarka Sengupta
  12. Amit Awasthi
  13. Soumen Basak
4 evaluations Published on
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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-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.

eToC

Deka 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.

Highlights

  • Aberrant 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 sentence

The non-canonical NF-κB pathway fuels intestinal inflammation by waning the tolerogenic β-catenin-Raldh2-retinoic acid axis in DCs.

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