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

多发性硬化(MS)是一种毁灭性的疾病，迫切需要更有效的预防和治疗 治疗。MS患者存在免疫反应失调(GM-CSF、IL-17A和IFNG)以及改变 与健康成年人相比，肠道微生物区系(粘液阿克曼氏菌患病率增加)。 此外，多发性硬化症的动物模型实验性自身免疫性脑脊髓炎(EAE)的研究结果强烈 提示肠道微生物区系参与了疾病的发病机制。然而，包括肠道微生物区系在内的 粘性阿克曼原虫对中枢神经系统的影响自身免疫功能低下 明白了。从Th17细胞(产生IL-17A和IL-17F的a、b T细胞)产生的IL-17A被认为是一种促细胞因子。 炎性细胞因子与EAE/MS有关，但IL-17A对肠道也有有益作用。这一差异 IL-17A在胃肠道和全身自身免疫中的作用尚不清楚。我们是第一个证明 IL-17A受体(IL-17RA)介导的上皮细胞信号转导控制微生物区系的定植。我们发现 肠道IL-17RA功能的丧失有助于共生生物失调，免疫细胞调节失调 对自身免疫的反应和易感性。然而，肠道IL-17RA如何调节微生物区系 调节全身性自身免疫的机制尚不清楚。这项提案的目标是描述 IL-17A-微生物组包括粘液弧菌-CNS轴在调节自身免疫性炎症中的作用，尤其是 EAE。我们积累了新的数据，即缺乏肠道IL-17RA信号会导致共生失调， GM-CSF反应失调以及对EAE的易感性增加。因此，基于我们令人兴奋的 初步数据，在目标1中，我们建议调查肠道内IL-17RA对微生物组的调控 EAE。在目标2中，我们将确定粘液弧菌是否调节脂肪酸代谢产物， 脑源性GM-CSF反应以及EAE发生率和评分在我们新的肠道上皮细胞特异性IL-1 17RA基因敲除小鼠。完成后，我们将了解微生物区系-Th17轴在 调节神经炎症。

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.