Non-canonical NF-κB signaling limits the tolerogenic β-catenin-Raldh2 axis in gut dendritic cells to exacerbate intestinal pathologies

• Published in: The EMBO journal Vol. 43; no. 18; pp. 3895 - 3915
• Main Authors: Deka, Alvina, Kumar, Naveen, Basu, Swapnava, Chawla, Meenakshi, Bhattacharya, Namrata, Ali, Sk Asif, Bhawna, Madan, Upasna, Kumar, Shakti, Das, Bhabatosh, Sengupta, Debarka, Awasthi, Amit, Basak, Soumen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25-07-2024
• Subjects: Biomedical and Life Sciences; EMBO12; EMBO19; EMBO37; Life Sciences; IgA; Retinoic Acid; Inflammation; Inflammatory Bowel Disease; RelB
• ISSN: 1460-2075; 0261-4189; 1460-2075
• DOI: 10.1038/s44318-024-00182-6

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.
Synopsis
Distorted functions of dendritic cells (DCs) have been implicated in aberrant intestinal inflammation, but the underlying mechanisms remain obscure. This study reveals that the non-canonical NF-κB pathway exacerbates intestinal inflammation by downregulating β-catenin-induced synthesis of Raldh2 in DCs.
Aberrant intestinal inflammation in mice is associated with non-canonical NF-κB signaling in gut DCs.
This pathway 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-specific defect in non-canonical NF-κB signaling causes β-catenin-dependent increase in luminal secretory IgA, fostering a eubiotic gut microbiome.
Inflammatory bowel-disease patients display a signature of elevated non-canonical NF-κB signaling in intestinal DCs.
A mechanism reducing Raldh2-promoted synthesis of retinoic acid compromises the tolerogenic potential of dendritic cells.