Non-canonical NF-κB signaling limits the tolerogenic β-catenin-Raldh2 axis in gut dendritic cells to exacerbate intestinal pathologies.
Alvina DekaNaveen KumarSwapnava BasuMeenakshi ChawlaNamrata BhattacharyaSk Asif Alinull BhawnaUpasna MadanShakti KumarBhabatosh DasDebarka SenguptaAmit AwasthiSoumen BasakPublished in: The EMBO journal (2024)
Dendritic cell (DC) dysfunction is known to exacerbate intestinal pathologies, but the mechanisms compromising DC-mediated immune regulation in this context remain unclear. Here, we show that intestinal dendritic cells from a mouse model of experimental colitis exhibit significant levels of noncanonical NF-κB signaling, which activates the RelB:p52 heterodimer. Genetic inactivation of this pathway in DCs alleviates intestinal pathologies in mice suffering from colitis. Deficiency of RelB:p52 diminishes transcription of Axin1, a critical component of the β-catenin destruction complex, reinforcing β-catenin-dependent expression of Raldh2, which imparts tolerogenic DC attributes by promoting retinoic acid synthesis. DC-specific impairment of noncanonical NF-κB signaling leads to increased colonic numbers of Tregs and IgA+ B cells, which promote luminal IgA production and foster eubiosis. Experimentally introduced β-catenin haploinsufficiency in DCs with deficient noncanonical NF-κB signaling moderates Raldh2 activity, reinstating colitogenic sensitivity in mice. Finally, inflammatory bowel-disease patients also display a deleterious noncanonical NF-κB signaling signature in intestinal DCs. In sum, we establish how noncanonical NF-κB signaling in dendritic cells can subvert retinoic acid synthesis to fuel intestinal inflammation.
Keyphrases
- dendritic cells
- signaling pathway
- oxidative stress
- regulatory t cells
- lps induced
- immune response
- pi k akt
- epithelial mesenchymal transition
- cell proliferation
- nuclear factor
- mouse model
- chronic kidney disease
- metabolic syndrome
- adipose tissue
- poor prognosis
- gene expression
- newly diagnosed
- high fat diet induced
- prognostic factors
- long non coding rna
- patient reported
- replacement therapy