Investigating the role of Akkermansia muciniphila and intestinal IL-17RA signaling in autoimmune inflammation

研究 Akkermansia muciniphila 和肠道 IL-17RA 信号在自身免疫炎症中的作用

• 批准号: 9808802
• 负责人: Pawan Kumar
• 金额: $ 19.61万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-05 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808802
• 关键词: Address; Adult; Animal Model; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacteria; CNS autoimmunity; Cells; Collaborations; Data; Disease; Enteral; Environment; Epithelial; Epithelial Cells; Experimental Autoimmune Encephalomyelitis; Fatty Acids; Germ Lines; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Host Defense; Immune; Immune response; Incidence; Inflammation; Inflammatory; Interleukin-17; Intestinal Diseases; Intestines; Knockout Mice; Knowledge; Mediating; Methanobrevibacter; Microbiology; Molecular; Mucolytics; Mucous body substance; Multiple Sclerosis; Mus; Nature; Neuraxis; Outcome; Pathogenesis; Pathway interactions; Play; Predisposition; Prevalence; Prevention; Regulation; Research Design; Role; Severities; Signal Transduction; T-Lymphocyte; Tamoxifen; Testing; Therapeutic; Universities; autoreactive T cell; base; cytokine; design; dysbiosis; experience; gastrointestinal; gastrointestinal epithelium; gut microbiome; gut microbiota; host microbiota; intestinal homeostasis; microbiome; microbiota; multiple sclerosis patient; neuroinflammation; novel; novel therapeutics; receptor; response; systemic autoimmunity; tool; villin

Multiple Sclerosis (MS) is a devastating disease which desperately needs more effective prevention and treatment. MS patients have dysregulated immune responses (GM-CSF, IL-17A and IFNg) as well as alterations in the gut microbiota (increased prevalence of Akkermansia muciniphila) compared to healthy adults. Additionally, findings in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, strongly suggest that the gut microbiota are involved in disease pathogenesis. However, how the gut microbiota including Akkermansia muciniphila (A. muciniphila) influences central nervous system (CNS) autoimmunity remains poorly understood. IL-17A derived from Th17 cells (a,b T cells producing IL-17A and IL-17F) is thought to be a pro- inflammatory cytokine implicated in EAE/MS, but IL-17A also has a beneficial effect in the gut. This differential role of IL-17A in gastrointestinal versus systemic autoimmunity remains unclear. We were first to demonstrate that IL-17A receptor (IL-17RA)-mediated epithelial cell signaling controls microbiota colonization. We found that abrogation of intestinal IL-17RA function contributes to commensal dysbiosis, dysregulated immune cell responses, and predisposition to autoimmunity. However, how intestinal IL-17RA regulation of microbiota modulates systemic autoimmunity remains unclear. The objective of this proposal is to characterize the role of the IL-17A-microbiome including A. muciniphila-CNS axis in regulating autoimmune inflammation, particularly EAE. We have accumulated novel data that lack of intestinal IL-17RA signaling leads to commensal dysbiosis, dysregulated GM-CSF responses as well as an enhanced susceptibility to EAE. Thus, based on our exciting preliminary data, in Aim 1 we propose to investigate how enteric IL-17RA regulation of the microbiome controls EAE. In Aim 2, we will determine whether A. muciniphila dysbiosis regulates fatty acid metabolites, encephalitogenic GM-CSF responses as well as EAE incidence and score in our novel gut epithelial-specific IL- 17RA knockout mice. Upon completion, we will understand the mechanisms for microbiota-Th17 axis in regulating neuroinflammation.

多发性硬化症（MS）是一种毁灭性的疾病，迫切需要更有效的预防， 治疗MS患者具有失调的免疫应答（GM-CSF、IL-17 A和IFNg）以及免疫应答的改变。 与健康成人相比，肠道微生物群（嗜粘蛋白阿克曼氏菌的患病率增加）。 此外，在实验性自身免疫性脑脊髓炎（EAE），MS的动物模型， 表明肠道微生物群参与疾病的发病机制。然而，肠道微生物群，包括 嗜胶阿克曼氏菌（Akkermansia mucinophila）是一种重要的真菌。嗜粘蛋白菌）影响中枢神经系统（CNS）的自身免疫仍然很差 明白来源于Th17细胞（产生IL-17 A和IL-17 F的a、B T细胞）的IL-17 A被认为是促细胞因子。 IL-17 A是EAE/MS中涉及的炎性细胞因子，但IL-17 A在肠道中也具有有益作用。此差分 IL-17 A在胃肠道与全身性自身免疫中的作用仍不清楚。我们首先证明了 IL-17A受体（IL-17RA）介导的上皮细胞信号传导控制微生物群定植。我们发现 肠道IL-17 RA功能的消除导致肠道生态失调、免疫细胞失调 反应和自身免疫易感性。然而，肠道IL-17RA如何调节微生物群 调节系统性自身免疫仍不清楚。本提案的目的是确定以下方面的作用： IL-17 A-微生物组包括A.在调节自身免疫性炎症，特别是 EAE。我们已经积累了新的数据，即缺乏肠道IL-17RA信号传导导致肠道生态失调， GM-CSF应答失调以及对EAE的易感性增强。因此，基于我们令人兴奋的 根据初步数据，在目标1中，我们提出研究肠道IL-17 RA如何调节微生物组控制 EAE。在目标2中，我们将确定是否A。嗜粘蛋白菌生态失调调节脂肪酸代谢物， 在我们的新型肠上皮特异性IL-10治疗中，致脑炎GM-CSF反应以及EAE发生率和评分 17RA基因敲除小鼠。完成后，我们将了解微生物群-Th17轴的机制， 调节神经炎症