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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：
10093034
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10093034
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 Epithelial Cells Flare Generations Genes Granzyme Hormones Human Immune Immune response Immunocompetent In Vitro Inflammatory Inflammatory Bowel Diseases Injections Interferon Type II Interleukin-17 Intestinal Diseases Intestines Intraperitoneal Injections Mediating Mediator of activation protein 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.

总结