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.

中文翻译：

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非经典 NF-κB 信号传导限制肠道树突状细胞中的耐受性 β-catenin-Raldh2 轴，从而加剧肠道病理。


众所周知，树突状细胞 (DC) 功能障碍会加剧肠道病理，但在这种情况下损害 DC 介导的免疫调节的机制仍不清楚。在这里，我们发现来自实验性结肠炎小鼠模型的肠树突状细胞表现出显着水平的非典型 NF-κB 信号传导，该信号激活 RelB:p52 异二聚体。 DC 中该通路的基因失活可减轻患有结肠炎的小鼠的肠道病理。 RelB:p52 的缺乏会减少 Axin1（β-连环蛋白破坏复合物的关键组成部分）的转录，从而增强 Raldh2 的 β-连环蛋白依赖性表达，从而通过促进视黄酸合成赋予耐受性 DC 属性。 DC 特异性非典型 NF-κB 信号传导损伤导致结肠 Tregs 和 IgA+ B 细胞数量增加，从而促进腔内 IgA 产生并促进优生。通过实验，在具有缺陷的非典型 NF-κB 信号传导的 DC 中引入 β-连环蛋白单倍体不足，可调节 Raldh2 活性，从而恢复小鼠的结肠炎敏感性。最后，炎症性肠病患者的肠道 DC 中也表现出有害的非典型 NF-κB 信号传导特征。总之，我们确定了树突状细胞中的非经典 NF-κB 信号传导如何破坏视黄酸合成从而加剧肠道炎症。