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发病机理中的作用，但目前尚不清楚IL-23在体内如何表达促进结肠炎。为了更好地研究免疫能力小鼠IL-23的生物学模型（R23FR小鼠），其中在肠中CX3CR1+细胞中促进IL-23的表达在低水平，在他莫昔芬（TAM）给药后。 IL-23通过饮食中溶解的TAM的重复循环诱导（饮食） 2019）与我们设施中使用的饮食不同（饮食5053）导致了类似于标记的结肠炎的发展人类溃疡性结肠炎。还观察到了在人类中观察到的浮雕周期（耀斑）和缓解周期在饮食转换时，在这些动物中。机械研究表明，促进的饮食转换标记了 R23FR小鼠及其同窝对照（FR小鼠）的微生物群的变化。结肠炎诱导和耀斑需要存在菌群和CD4+ T细胞。来自肠系膜LN或结肠的CD4+ T细胞 R23FR小鼠缓解时，而不是对照组的小鼠，将疾病转移到抹布 - / - 小鼠，但仅在当时受体小鼠接受了2019年的饮食，表明CD4+ T细胞的先前启动。单细胞转录组对疾病诱导的CD4+ T细胞的分析证明了表达不同种群的存在细胞因子IL-17，IL-22，IFNγ，趋化因子和细胞毒性分子。缺乏基因的小鼠和抗体封锁表明IL-22和IL-17对于疾病发展并不重要，表明存在替代效应器机制。实际上，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，疾病需要上皮细胞的MHC-II表达发展。使用这种新型的小鼠模型，我们将测试一般假设，即饮食发生变化与IL-23的低水平表达相似，导致对共生菌群的免疫反应或他们的产品。在AIM 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AIM 2中，我们将定义饮食变化和IL-23表达如何促进效应子免疫回答。

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.

DOI：
10.1016/j.immuni.2023.11.011
发表时间：
2023-12
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：
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

CCR6 Deficiency Increases Infarct Size after Murine Acute Myocardial Infarction.

DOI：
10.3390/biomedicines9111532
发表时间：
2021-10-25
期刊：
Biomedicines
影响因子：
4.7
作者：
Schumacher D;Liehn EA;Singh A;Curaj A;Wijnands E;Lira SA;Tacke F;Jankowski J;Biessen EAL;van der Vorst EPC
通讯作者：
van der Vorst EPC