Mechanisms associated with diet-induced colitis

饮食诱发结肠炎的相关机制

基本信息

批准号：
10553265
负责人：
SERGIO A. LIRA
金额：
$ 58.89万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10553265
关键词：
Adoptive Transfer Animal Model Animals Antibodies Antigens Bacteria Biology CD4 Positive T Lymphocytes Cecum Cell physiology Cell-Mediated Cytolysis Cells Chronic Colitis Colon Cytotoxic T-Lymphocytes Development Diet Disease Disease remission Environmental Risk Factor Epithelial Cells Epithelium Flare Generations Genes Granzyme Hormones Human IL17 gene Immune Immune response Immunocompetent In Vitro Inflammatory Inflammatory Bowel Diseases Injections Interferon Type II Intestinal Diseases Intestines Intraperitoneal Injections Mediating Mediator Mesentery Microbe Mus Pathogenesis Pathway interactions Population Proteins Relapse Research Personnel Role Severity of illness Stress Tamoxifen Testing Transgenic Animals Ulcerative Colitis Up-Regulation chemokine commensal microbes cytokine cytotoxic experimental study in vivo insight interleukin-22 interleukin-23 intestinal epithelium microbiota mouse model novel novel therapeutic intervention perforin single-cell RNA sequencing transcriptomics

项目摘要

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.

概括许多研究支持IL-23在IBD发病机制中的作用，但尚不清楚IL-23在体内的表达情况为了更好地研究免疫活性小鼠中 IL-23 的生物学特性，我们培育了一种小鼠。模型（R23FR 小鼠），其中肠道 CX3CR1+ 细胞中 IL-23 的表达在低水平上得到促进，通过将 TAM 溶解在饮食中进行重复循环，施用他莫昔芬 (TAM) 来诱导 IL-23。 2019）与我们设施中使用的饮食（饮食 5053）不同，导致出现明显的结肠炎，类似于还观察到人类溃疡性结肠炎的复发（发作）和缓解周期。机制研究表明，饮食转换对这些动物有显着的促进作用。 R23FR 小鼠及其同窝对照小鼠（FR 小鼠）的微生物群变化。需要存在来自肠系膜淋巴结或结肠的微生物群和 CD4+ T 细胞。缓解时的 R23FR 小鼠（而非对照小鼠）将疾病转移至 Rag-/- 小鼠，但仅当受体小鼠接受了 2019 年的饮食，表明 CD4+ T 细胞之前已启动。对诱发疾病的 CD4+ T 细胞的分析证明了表达不同群体的存在细胞因子 IL-17、IL-22、IFNγ、趋化因子和细胞毒性分子基因缺陷小鼠和抗体。阻断表明 IL-22 和 IL-17 对于疾病发展并不重要，这表明存在事实上，体外实验表明，来自 R23FR 小鼠的 CD4+ 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。使用这种新颖的小鼠模型，我们将测试饮食发生变化的一般假设。同时 IL-23 的低水平表达导致对共生微生物群的免疫反应在目标 1 中，我们将定义饮食改变和 IL-23 表达如何促进免疫。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。回应。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders.

循环的衰老骨髓细胞浸润大脑并导致组织细胞疾病的神经变性。

DOI：
10.1016/j.immuni.2023.11.011
发表时间：
2023-12-01
期刊：
Immunity
影响因子：
32.4
作者：
C. M. Wilk;F. Cathomas;Orsolya Török;Jessica Le Berichel;Matthew D. Park;Camille Bigenwald;George R. Heaton;Pauline Hamon;Leanna Troncoso;B. Scull;Diana K. Dangoor;Aymeric Silvin;Ryan Fleischmann;M. Belabed;Howard Lin;Elias Merad Taouli;Steffen Boettcher;Long Li;Antonio Aubry;M. Manz;Julia K. Kofler;Zhenyu Yue;Sérgio A. Lira;Florent Ginhoux;J. Crary;Kenneth L. McClain;Jennifer L. Picarsic;Scott J Russo;Carl E. Allen;M. Merad
通讯作者：
M. Merad

CCR6 Deficiency Increases Infarct Size after Murine Acute Myocardial Infarction.

CCR6 缺乏会增加小鼠急性心肌梗塞后的梗塞面积。

DOI：
发表时间：
2021-10-25
期刊：
影响因子：
4.7
作者：
Schumacher, David;Liehn, Elisa A;Singh, Anjana;Curaj, Adelina;Wijnands, Erwin;Lira, Sergio A;Tacke, Frank;Jankowski, Joachim;Biessen, Erik A L;van der Vorst, Emiel P C
通讯作者：
van der Vorst, Emiel P C

Tumor-Infiltrating Regulatory T-cell Accumulation in the Tumor Microenvironment Is Mediated by IL33/ST2 Signaling.

肿瘤微环境中的肿瘤浸润调节性 T 细胞积聚由 IL33/ST2 信号传导介导。

DOI：
发表时间：
2020-11
期刊：
影响因子：
10.1
作者：
Son, Jimin;Cho, Jae;Park, Hyo Jin;Moon, Jihyun;Park, Seyeon;Lee, Hoyoung;Lee, Jeewon;Kim, Gamin;Park, Su;Lira, Sergio A;Mckenzie, Andrew N;Kim, Hye Young;Choi, Cheol Yong;Lim, Yong Taik;Park, Seong Yong;Kim, Hye Ryun;Park, Su
通讯作者：
Park, Su