Objective Nuclear receptors are known to regulate both immune and barrier functions in the GI tract. The nuclear orphan receptor NR2F6 has been shown to suppress the expression of proinflammatory cytokines in T lymphocytes. NR2F6 gene expression is reduced in patients with IBS or UC, but its functional role and tissue dependency in healthy and inflamed gut have not yet been investigated. Design Intestinal inflammation was induced in wild-type, Nr2f6-deficient, Rag1-deficient or bone marrow-reconstituted mice by administration of chemical (dextran sodium sulfate (DSS)) and immunogenic (T cell transfer) triggers. Disease phenotypes were investigated by survival, body weight, colon length and analysis of immune cell infiltrates. Additionally, histology, intestinal permeability, tight junction proteins, bacterial fluorescence in situ hybridisation, apoptosis, cell proliferation and mucus production were investigated. Results Nr2f6-deficient mice were highly susceptible to DSS-induced colitis characterised by enhanced weight loss, increased colonic tissue destruction and immune cell infiltration together with enhanced intestinal permeability and reduced Muc2 expression. T cell transfer colitis and bone marrow reconstitution experiments demonstrated that disease susceptibility was not dependent on the expression of Nr2f6 in the immune compartment but on the protective role of NR2F6 in the intestinal epithelium. Mechanistically, we show that NR2F6 binds to a consensus sequence at −2 kb of the Muc2 promoter and transactivates Muc2 expression. Loss of NR2F6 alters intestinal permeability and results in spontaneous late-onset colitis in Nr2f6-deficient mice. Conclusion We have for the first time identified a fundamental and non-redundant role of NR2F6 in protecting gut barrier homeostasis.

中文翻译：

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核孤儿受体 NR2F6 作为预防实验性小鼠结肠炎的保护措施

目的 众所周知，核受体可调节胃肠道中的免疫和屏障功能。核孤儿受体 NR2F6 已被证明可抑制 T 淋巴细胞中促炎细胞因子的表达。IBS 或 UC 患者的 NR2F6 基因表达降低，但尚未研究其在健康和发炎肠道中的功能作用和组织依赖性。设计 通过施用化学物质（葡聚糖硫酸钠 (DSS)）和免疫原性（T 细胞转移）触发器，在野生型、Nr2f6 缺陷型、Rag1 缺陷型或骨髓重建小鼠中诱导肠道炎症。通过存活率、体重、结肠长度和免疫细胞浸润分析来研究疾病表型。此外，组织学、肠道通透性、紧密连接蛋白、细菌荧光原位杂交、对细胞凋亡、细胞增殖和粘液产生进行了研究。结果 Nr2f6 缺陷小鼠对 DSS 诱导的结肠炎高度敏感，其特征是体重减轻、结肠组织破坏和免疫细胞浸润增加，以及肠道通透性增强和 Muc2 表达降低。T 细胞转移性结肠炎和骨髓重建实验表明，疾病易感性不取决于免疫区室中 Nr2f6 的表达，而是取决于 NR2F6 在肠上皮中的保护作用。从机制上讲，我们表明 NR2F6 与 Muc2 启动子 -2 kb 处的共有序列结合并反式激活 Muc2 表达。NR2F6 的缺失会改变肠道通透性，并导致 Nr2f6 缺陷小鼠的自发性迟发性结肠炎。