Mechanisms associated with diet-induced colitis

总结 许多研究支持IL-23在IBD发病机制中的作用，但尚不清楚IL-23在体内的表达如何影响IBD的发病机制。 促进结肠炎。为了更好地研究IL-23在免疫活性小鼠中的生物学，我们开发了一种小鼠， 模型（R23 FR小鼠），其中IL-23的表达在肠中的CX 3CR 1+细胞中以低水平被促进， 三苯氧胺（TAM）。通过溶解在饮食（饮食）中的TAM的重复循环的IL-23诱导 2019年）与我们机构使用的饮食（饮食5053）不同，导致发生明显的结肠炎， 人类的溃疡性结肠炎还观察到在人类中观察到的复发（发作）和缓解周期 在这些动物的饮食转换。机制研究表明，饮食转换促进了显著的 R23 FR小鼠及其同窝对照（FR小鼠）的微生物群的变化。结肠炎诱导和发作 需要微生物和CD 4 + T细胞的存在。CD 4 + T细胞来自肠系膜LN或结肠， 缓解期的R23 FR小鼠将疾病转移给Rag-/-小鼠，但只有当R23 FR小鼠的免疫反应停止时，R23 FR小鼠的免疫反应才停止。 接受者小鼠接受饮食2019，表明先前的CD 4 + T细胞致敏。单细胞转录组 对疾病诱导性CD 4 + T细胞的分析表明，存在不同的群体表达 细胞因子IL-17、IL-22、IFNγ、趋化因子和细胞毒性分子。基因缺陷小鼠与抗体 阻断表明IL-22和IL-17对疾病发展并不重要，这表明存在IL-22和IL-17。 替代效应器机制。事实上，体外实验表明，来自R23 FR小鼠的CD 4 + T细胞可以 直接杀死肠上皮细胞。最后，上皮细胞表达MHC-II是疾病发生所必需的。 发展使用这种新的小鼠模型，我们将测试一般的假设，即饮食发生变化， 同时IL-23的低水平表达导致对肠道微生物群的免疫应答 或他们的产品。在目标1中，我们将定义饮食变化和IL-23表达如何促进免疫 启动在目标2中，我们将定义饮食变化和IL-23表达如何促进效应免疫 应答

SUMMARY Many studies support a role for IL-23 in the pathogenesis of IBD, but it is unclear how IL-23 expression in vivo promotes colitis. To better study the biology of IL-23 in immune-competent mice we have developed a mouse model (R23FR mice) in which expression of IL-23 is promoted at low levels in CX3CR1+ cells in the intestine, upon administration of tamoxifen (TAM). IL-23 induction via repeated cycles of TAM dissolved in a diet (diet 2019) different from the diet used in our facility (diet 5053) led to development of marked colitis that resembled ulcerative colitis in humans. Cycles of relapse (flares) and remission, observed in humans, were also observed in these animals upon diet switch. Mechanistic studies demonstrated that the diet switch promoted marked changes in the microbiota of R23FR mice and their littermate controls (FR mice). Colitis induction and flares required the presence of the microbiota and CD4+ T cells. CD4+ T cells from the mesenteric LN or colon of R23FR mice at remission, but not those of controls, transferred disease to Rag-/- mice, but only when the recipient mice received diet 2019, suggesting previous priming of the CD4+ T cells. Single cell transcriptomic analysis of the disease-inducing CD4+ T cells demonstrated the existence of distinct populations expressing the cytokines IL-17, IL-22, IFNγ, chemokines, and cytotoxic molecules. Gene-deficient mice and antibody blockade showed that IL-22 and IL-17 were not critical for disease development, suggesting the existence of alternative effector mechanisms. Indeed, in vitro experiments showed that CD4+ T cells from R23FR mice can directly kill intestinal epithelial cells. Finally, MHC-II expression by epithelial cells was required for disease development. Using this novel mouse model we will test the general hypothesis that changes in diet occurring simultaneously with low level expression of IL-23 result in an immune response to the commensal microbiota or their products. In Aim 1 we will define how diet changes and IL-23 expression promote immune priming. In Aim 2 we will define how diet changes and IL-23 expression promote effector immune responses.