Mechanisms associated with diet-induced colitis

摘要 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在体内是如何表达的 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作用，我们开发了一种小鼠 肠道CX3CR1细胞低水平促进IL-23表达的模型(R23FR小鼠) 服用三苯氧胺()。在饮食中的反复循环诱导IL-23 2019年)与我们设施中使用的饮食(饮食5053)不同导致明显的结肠炎 人类的溃疡性结肠炎。在人类身上观察到的复发(耀斑)和缓解的周期也被观察到。 在这些动物中，饮食发生了变化。机械学研究表明，饮食转换促进了显著的 R23FR小鼠及其产仔对照(FR小鼠)微生物区系的变化。结肠炎诱导和红肿 需要微生物区系和CD4T细胞的存在。肠系膜LN或结肠的CD4T细胞 R23FR小鼠在缓解期，但不是对照组的小鼠，将疾病传播给RAG-/-小鼠，但只有当 受体小鼠接受了2019年的饮食，这表明之前已经启动了CD4T细胞。单细胞转录 对致病的CD4T细胞的分析表明，存在不同的人群表达 细胞因子IL-17、IL-22、干扰素γ、趋化因子和细胞毒分子。基因缺陷小鼠及其抗体 Blockade表明IL-22和IL-17在疾病发展中不是关键，这表明 另一种效应器机构。事实上，体外实验表明，来自R23FR小鼠的CD4T细胞可以 直接杀死肠道上皮细胞。最后，疾病需要上皮细胞表达MHC-II 发展。使用这一新的小鼠模型，我们将检验饮食发生变化的普遍假设 同时，IL-23的低水平表达导致对共生微生物区系的免疫反应 或者他们的产品。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 引爆。在目标2中，我们将定义饮食变化和IL-23表达如何促进效应器免疫 回应。

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.