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Orchestrating intestinal immunity through microbiota-CX3CR1+ cell interactions

通过微生物群-CX3CR1 细胞相互作用协调肠道免疫

基本信息

批准号：
10735384
负责人：
GRETCHEN E DIEHL
金额：
$ 53.1万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-02 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735384
关键词：
Address Animal Disease Models Anti-Inflammatory Agents CD4 Positive T Lymphocytes Calibration Cell Communication Cell Death Cell physiology Cells Characteristics Chronic Communicable Diseases Communities Dendritic Cells Development Disease Escherichia coli Event Generations Goals Homeostasis Human Immune Immune response Immune system Immunity In Vitro Individual Inflammasome Inflammatory Inflammatory Bowel Diseases Inflammatory Response Intestines Left Macrophage Maintenance Microbe Molecular Mucous Membrane Mus Pathogenicity Pathologic Pathology Pathway interactions Penetration Physiological Play Population Predisposition Production Regulation Regulatory Pathway Role Shapes Signal Transduction Site T cell response T-Lymphocyte Testing Tissues Work antimicrobial cell type commensal microbes cytokine dysbiosis enteric infection gut inflammation gut microbiota immune activation immune function immune system function improved improved outcome in vivo Model intestinal barrier intestinal epithelium intestinal homeostasis intestinal injury microbial microbiota microorganism mucosal microbiota normal microbiota novel pathogen protective effect repaired response restraint

项目摘要

Project Summary The microbiota provides many key signals that support development and functioning of the immune system. Interactions between host and microbiota allows for proper induction of immune responses against pathogens. These interactions are also necessary to limit inflammatory immune responses against the microbiota which, if left unchecked, will result in inflammatory conditions including inflammatory bowel disease. Many intestinal cell types including immune cells and the intestinal epithelium recognize and respond to the microbiota. It is unclear how such signals are integrated to support homeostasis. In humans as well as in animal models of disease, compositional changes in the microbiota, also known as dysbiosis, correlate with increased susceptibility to inflammatory disease. Understanding the role of individual microbes within the community would allow for the development of novel mechanistic approaches to restore homeostasis in the case of inflammatory disease. We identified a subset of mucosa associated E. coli that induce intestinal macrophage production of IL-1b. This activates innate protection of the intestinal barrier but also drives proinflammatory T cell responses against these E. coli. Specific characteristics of these E. coli as well as how they interact with the host immune system likely drives these responses. In Aim 1 of the proposed work, we will use in vitro and in vivo models to determine how these E. coli activate IL-1b production. In Aim 2 we will define the regulation and consequence of T cell responses against these E. coli. Together, these studies will identify molecular crosstalk between intestinal microbes and immune system that underlie pro-inflammatory responses against the microbiota. Understanding these signals will allow us to identify mechanisms for regulating these pathways and reducing unnecessary intestinal inflammation.

项目摘要微生物群提供了许多支持免疫系统发育和功能的关键信号。宿主和微生物群之间的相互作用允许适当诱导针对病原体的免疫应答。这些相互作用对于限制针对微生物群的炎症免疫应答也是必要的，如果如果不加以控制，将导致炎症性疾病，包括炎症性肠病。许多肠细胞包括免疫细胞和肠上皮细胞在内的类型识别并响应微生物群。目前还不清楚这些信号是如何整合以支持体内平衡的。在人类和动物疾病模型中，微生物群中的组成变化，也称为生态失调，与对微生物的易感性增加有关。炎症性疾病。了解单个微生物在群落中的作用将允许开发新的机制方法来恢复炎症性疾病的体内平衡。我们鉴定了粘膜相关E.大肠杆菌，诱导肠巨噬细胞产生IL-1b。这激活肠道屏障的先天保护，但也驱动促炎性T细胞反应， E.杆菌这些E.以及它们如何与宿主免疫系统相互作用驱动这些反应。在拟议工作的目标1中，我们将使用体外和体内模型来确定如何这些E. coli激活IL-1b的产生。在目标2中，我们将定义T细胞应答的调节和后果这些E。杆菌总之，这些研究将确定肠道微生物之间的分子串扰，免疫系统是针对微生物群的促炎反应的基础。了解这些信号将使我们能够确定调节这些途径的机制，并减少不必要的肠道炎症