Retinoic acid (RA), a dietary vitamin A metabolite, is crucial in maintaining intestinal homeostasis. RA acts on intestinal leukocytes to modulate their lineage commitment and function. Although the role of RA has been characterized in immune cells, whether intestinal epithelial cells (IECs) rely on RA signaling to exert their immune-regulatory function has not been examined. Here we demonstrate that lack of RA receptor α (RARα) signaling in IECs results in deregulated epithelial lineage specification, leading to increased numbers of goblet cells and Paneth cells. Mechanistically, lack of RARα resulted in increased KLF4⁺ goblet cell precursors in the distal bowel, whereas RA treatment inhibited klf4 expression and goblet cell differentiation in zebrafish. These changes in secretory cells are associated with increased Reg3g, reduced luminal bacterial detection, and an underdeveloped intestinal immune system, as evidenced by an almost complete absence of lymphoid follicles and gut resident mononuclear phagocytes. This underdeveloped intestinal immune system shows a decreased ability to clear infection with Citrobacter rodentium. Collectively, our findings indicate that epithelial cell-intrinsic RARα signaling is critical to the global development of the intestinal immune system.

中文翻译：

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肠上皮细胞特异性 RARα 耗竭导致上皮细胞稳态异常和免疫系统发育不全。

视黄酸 (RA) 是一种膳食维生素 A 代谢物，对于维持肠道稳态至关重要。RA 作用于肠道白细胞以调节其谱系定型和功能。尽管 RA 的作用已在免疫细胞中得到表征，但肠上皮细胞 (IEC) 是否依赖 RA 信号来发挥其免疫调节功能尚未得到检验。在这里，我们证明 IEC 中缺乏 RA 受体 α (RARα) 信号导致上皮谱系规范失调，导致杯状细胞和潘氏细胞数量增加。从机制上讲，缺乏 RARα 会导致 KLF4 ^+增加远端肠中的杯状细胞前体，而 RA 治疗抑制斑马鱼中的 klf4 表达和杯状细胞分化。分泌细胞的这些变化与 Reg3g 增加、管腔细菌检测减少和肠道免疫系统发育不全有关，几乎完全没有淋巴滤泡和肠道常驻单核吞噬细胞就是证明。这种不发达的肠道免疫系统显示出清除柠檬酸杆菌感染的能力下降。总的来说，我们的研究结果表明，上皮细胞固有的 RARα 信号对肠道免疫系统的全面发展至关重要。