Vitamin D Receptor-Dependent Signaling Protects Mice From Dextran Sulfate Sodium-Induced Colitis
Vitamin D Receptor-Dependent Signaling Protects Mice From Dextran Sulfate Sodium-Induced Colitis
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DOI：
10.1210/en.2016-1913
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发表时间：
2017-06-01
期刊：
影响因子：
4.8
通讯作者：
Fleet, James C.
中科院分区：
文献类型：
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作者：
Wang, Fa;Johnson, Robert L.;Fleet, James C.
低维生素 D 状态会加剧实验性结肠炎，但结肠炎中的维生素 D 反应细胞尚未明确。我们假设维生素 D 在结肠炎期间的结肠上皮细胞和非上皮细胞中具有不同的作用。我们使用结肠上皮细胞 (CEC-VDRKO) 或非肠上皮细胞 (NEC-VDRKO) 中维生素 D 受体 (VDR) 缺失的小鼠来测试这一假设。八周大的小鼠用 1.35% 葡聚糖硫酸钠 (DSS) 处理 5 天，然后在去除 DSS 后 2 或 10 天实施安乐死。 DSS 导致体重减轻并增加疾病活动指数和脾脏大小。这种反应在 NEC-VDRKO 小鼠中增强，但在 CECVDRKO 小鼠中没有增强。在两种小鼠模型中，DSS 诱导的结肠上皮损伤和免疫细胞浸润评分均有所增加。尽管在对照和CEC-VDRKO小鼠中给予DSS后2至10天内上皮愈合，但在去除DSS后10天NEC-VDRKO小鼠中上皮损伤仍然很高，表明上皮愈合延迟。第 10 天，NEC-VDRKO 小鼠结肠中促炎性 M1 巨噬细胞 (M phi) 细胞因子肿瘤坏死因子-α、一氧化氮合酶 2 和白细胞介素-1 β 的基因表达水平显着升高。小鼠腹膜 M phi 的体外实验表明，1,25 二羟基维生素 D 直接 抑制 M1 极化，促进 M2 极化，并调节 M phi 表型转向 M2 和远离 M1 表型。我们的数据揭示了结肠炎期间维生素 D 信号在结肠上皮以及结肠微环境中的非上皮细胞中的独特保护作用（即 M phi 生物学的调节）。
Low vitamin D status potentiates experimental colitis, but the vitamin D-responsive cell in colitis has not been defined. We hypothesized that vitamin D has distinct roles in colonic epithelial cells and in nonepithelial cells during colitis. We tested this hypothesis by using mice with vitamin D receptor (VDR) deletion from colon epithelial cells (CEC-VDRKO) or nonintestinal epithelial cells (NEC-VDRKO). Eight-week-old mice were treated with 1.35% dextran sulfate sodium (DSS) for 5 days and then euthanized 2 or 10 days after removal of DSS. DSS induced body weight loss and increased disease activity index and spleen size. This response was increased in NEC-VDRKO mice but not CECVDRKO mice. DSS-induced colon epithelial damage and immune cell infiltration scores were increased in both mouse models. Although the epithelium healed between 2 and 10 days after DSS administration in control and CEC-VDRKO mice, epithelial damage remained high in NEC-VDRKO mice 10 days after removal of DSS, indicating delayed epithelial healing. Gene expression levels for the proinflammatory, M1 macrophage (M phi) cytokines tumor necrosis factor-alpha, nitric oxide synthase 2, and interleukin-1 beta were significantly elevated in the colon of NEC-VDRKO mice at day 10. In vitro experiments in murine peritoneal M phi s demonstrated that 1,25 dihydroxyvitamin D directly inhibited M1 polarization, facilitated M2 polarization, and regulated M phi phenotype switching toward the M2 and away from the M1 phenotype. Our data revealed unique protective roles for vitamin D signaling during colitis in the colon epithelium as well as nonepithelial cells in the colon microenvironment (i.e., modulation of M phi biology).