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

• 批准号: 10318457
• 负责人: GRETCHEN E DIEHL
• 金额: $ 44.25万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-02 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318457
• 关键词: Address; Adopted; Animals; Anti-Inflammatory Agents; Antibiotics; Automobile Driving; Bacteria; Bacterial Infections; Binding; Biological Assay; Cell Communication; Cells; Clinical; Communities; Development; Disease; Escherichia coli; Excision; Failure; Genes; Homeostasis; Human; Immune; Immune response; Immune system; Immunity; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-10; Intestines; Lamina Propria; Lead; Lymph; Mediating; Microbe; Molecular; Mononuclear; Mouse Strains; Mus; Pathogenicity; Pathology; Pathway interactions; Patients; Phagocytes; Play; Population; Production; Proteins; Regulation; Regulatory T-Lymphocyte; Role; Shapes; Signal Pathway; Signal Transduction; T cell response; antimicrobial; base; chemokine receptor; commensal microbes; cytokine; design; enteric pathogen; epithelial repair; experimental study; gastrointestinal infection; gene product; genetic element; gut microbiota; human disease; immune function; in vivo; inflammatory disease of the intestine; insight; intestinal barrier; intestinal homeostasis; member; mesenteric lymph node; microbial; microbiota; microorganism; migration; normal microbiota; novel; pathogen; pathogenic bacteria; prevent; response; restoration; trafficking

Project Summary The development and responsiveness of the mammalian immune system is shaped by a dynamic interaction between the host immune system and the resident microbiota. The development of a host of human diseases is associated with shifts in the microbiota alongside alterations in the intestinal immune responses. We previously established that a population of mononuclear phagocytes (MNPs) expressing the CX3CR1 chemokine receptor play a central role in the immune system's responses to the microbiota and regulation of intestinal homeostasis. In the presence of the microbiota, CX3CR1+ MNPs limit inflammatory immune responses against both pathogenic bacterial infections and the microbiota itself in addition to promoting Treg responses against soluble fed proteins. In contrast, removal of the microbiota promotes inflammatory T cell responses brought about by dysregulation in a number of CX3CR1+ MNP functions, including production of the anti-inflammatory cytokine IL-10 and clearance of intracellular bacteria. Further dysregulation of CX3CR1+ MNP function is associated with pathology in inflammatory conditions such as inflammatory bowel disease (IBD). We therefore hypothesize that under normal conditions, specific members of the microbiota activate cellular pathways in CX3CR1+ MNPs responsible for limiting intestinal inflammation by restraining inflammatory T cell responses and promoting intestinal mucosal barrier function. Conversely, the shifted microbiota composition frequently associated with gastrointestinal infection or inflammatory disorders such as IBD provide alternative signals to CX3CR1+ MNPs, driving them to pathogen clearance and promoting intestinal inflammation. Reestablishing the normal microbiota should then direct CX3CR1+ MNPs to restore intestinal homeostasis. To address the in vivo role for CX3CR1+ MNPs in the induction of intestinal immune responses, we generated novel mouse strains in which CX3CR1+ MNPs can be selectively depleted. We will use these mice in conjunction with ex vivo assays to study the regulation of homeostatic functions in CX3CR1+ MNPs by the microbiota as a whole as well as by select individual members. In Aim 1, we will determine how the microbiota modulates CX3CR1+ MNP function to promote regulatory T cell responses and limit inflammation. In Aim 2, we will determine the impact of individual members of the microbiota and their gene products on CX3CR1+ MNP- induced anti-inflammatory T cell responses. At the conclusion of these studies, we will have identified and characterized cellular pathways regulated by the microbiota that are designed to limit inflammation as well as the microbial gene products responsible for the induction of these anti-inflammatory pathways. Together, these studies will provide critical insights into the modulation of anti-inflammatory responses in the intestine by the microbiota and will facilitate the identification of additional clinical targets for promoting and reestablishing intestinal homeostasis.

项目概要 哺乳动物免疫系统的发育和反应是由动态相互作用决定的 宿主免疫系统和常驻微生物群之间。许多人类疾病的发展 与微生物群的变化以及肠道免疫反应的改变有关。我们 先前确定表达 CX3CR1 的单核吞噬细胞 (MNP) 群体 趋化因子受体在免疫系统对微生物群的反应和调节中发挥着核心作用 肠道稳态。在微生物群存在的情况下，CX3CR1+ MNP 限制炎症免疫 除了促进 Treg 外，还对病原菌感染和微生物群本身做出反应 针对可溶性饲喂蛋白质的反应。相反，去除微生物群会促进炎症 T 细胞的产生 由许多 CX3CR1+ MNP 功能失调引起的反应，包括产生 抗炎细胞因子 IL-10 和细胞内细菌的清除。 CX3CR1+ MNP 进一步失调 功能与炎症性疾病（例如炎症性肠病（IBD））的病理学相关。我们 因此假设在正常条件下，微生物群的特定成员会激活细胞 CX3CR1+ MNPs 中的通路负责通过抑制炎症 T 细胞来限制肠道炎症 反应并促进肠粘膜屏障功能。相反，改变的微生物群组成 经常与胃肠道感染或炎症性疾病（如 IBD）相关的药物提供了替代方案 向 CX3CR1+ MNP 发出信号，驱动它们清除病原体并促进肠道炎症。 重建正常微生物群应指导 CX3CR1+ MNP 恢复肠道稳态。到 为了解决 CX3CR1+ MNP 在诱导肠道免疫反应中的体内作用，我们生成了 CX3CR1+ MNP 可以被选择性耗尽的新型小鼠品系。我们将使用这些小鼠 与离体测定相结合，研究 CX3CR1+ MNP 中稳态功能的调节 微生物群作为一个整体以及选定的个体成员。在目标 1 中，我们将确定微生物群如何 调节 CX3CR1+ MNP 功能，促进调节性 T 细胞反应并限制炎症。在目标 2 中，我们 将确定微生物群的个体成员及其基因产物对 CX3CR1+ MNP- 诱导抗炎 T 细胞反应。在这些研究结束时，我们将确定并 由微生物群调节的特征性细胞途径，旨在限制炎症以及 负责诱导这些抗炎途径的微生物基因产物。在一起，这些 研究将为肠道抗炎反应的调节提供重要见解 微生物群，并将有助于确定其他临床目标，以促进和重建 肠道稳态。