Remyelination in a mouse model of multiple sclerosis resulting from microbial metabolite sensor disruption

微生物代谢传感器破坏引起的多发性硬化症小鼠模型中的髓鞘再生

• 批准号: 10606270
• 负责人: Andrea Rae Merchak
• 金额: $ 1.95万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606270
• 关键词: Address; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Aryl Hydrocarbon Receptor; Autoimmune Diseases; Autoimmunity; Axon; Back; CD4 Positive T Lymphocytes; Cecum; Cell Differentiation process; Cells; Central Nervous System; Central Nervous System Diseases; Chronic Phase; Chronic Phase of Disease; Classification; Communication; Complex; Data; Demyelinations; Disease; Environmental Risk Factor; Epithelium; Etiology; Exhibits; Experimental Autoimmune Encephalomyelitis; Exposure to; Feedback; Feeds; Frequencies; Gastrointestinal tract structure; Genetic; Genetic Predisposition to Disease; Homeostasis; Immune; Immune response; Immune system; Immunosuppression; In Vitro; Infiltration; Interleukin-12; Knock-out; Knockout Mice; Knowledge; Lesion; Link; Lung; Macrophage; Macrophage Activation; Mediating; Mediator; Metabolic; Modeling; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; Nervous System; Oligodendroglia; Paralysed; Pathogenesis; Patients; Pattern; Peripheral; Production; Recovery; Recurrence; Relapse; Research; Role; Severities; Signal Transduction; Site; Skin; Source; Spinal Cord; Symptoms; T-Lymphocyte; Tissues; Toxin; Transmission Electron Microscopy; Work; autoimmune pathogenesis; commensal microbes; cytokine; experimental study; fitness; gut microbiome; gut-brain axis; immune activation; immunoregulation; in vivo; in vivo Model; inflammatory milieu; interleukin-12 receptor; knockout animal; microbial; microbiome; microbiota; motor function recovery; mouse model; multiple sclerosis patient; myelination; novel; oligodendrocyte progenitor; prevent; remyelination; response; sensor; small molecule; stem cells; targeted treatment; tool; transcription factor

ABSTRACT: Multiple sclerosis (MS) is a debilitating and complex autoimmune disorder in which the myelin within the central nervous system is attacked. The frequency and severity of relapses are highly variable and are linked to both environmental and genetic etiologies. Compelling data obtained from patients and animal models of MS show that the gut microbiome is a critical mediator of pathogenesis. While the relationship between the commensal microbiota and the immune system is well established, the precise mechanisms underlying microbiota-immune crosstalk seen in MS remain unclear. In this proposed study, I suggest a mechanistic link between microbiome and myelin recovery in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). A sensor of microbial metabolites called the aryl hydrocarbon receptor (AHR) is a transcription factor that modulates immune and metabolic homeostasis at barrier tissues including the skin, lungs, and, importantly, the gastrointestinal tract. AHR activity in T cells has the capacity to modify the gut microbiome as well as modify immune cell fitness. Previous work has focused on germ-line AHR knockouts or cell specific knock out in the nervous system; however, I have produced a CD4 T cell specific AHR knockout mouseline, and these animals exhibit a microbiome-dependent recovery from EAE. These mice have increased myelin coverage after initial paralysis and decreased IL-12 in the spinal cord at peak of disease. Additionally, I have found that IL-12 reduces oligodendrocyte progenitor cell (OPC) differentiation into myelinating oligodendrocytes in vitro. Under this proposal, I aim to use my previously described model of recovery, T cell Ahr knockout mice, to 1) characterize the myelin dynamics in a remyelinating lesions and 2) determine the role of IL-12 as an intermediary between the immune system and myelinating oligodendrocyte progenitor cells. I will determine whether myelin recovery is the result of OPC differentiation or of mature oligodendrocyte recovery using transmission electron microscopy and lineage tracing. I will attempt to understand the source of the IL-12 in this model and the cell intrinsic signaling cascades in OPCs and oligodendrocytes affected by IL-12. Finally, I will utilize an IL-12 receptor knockout to understand the role of IL-12 during myelination in vivo. Understanding this mechanistic link between the microbiome and the central nervous system will have implications for early stage MS patients recovering from relapsing symptoms. By establishing the direct and indirect effects of an environmental sensor (AHR) on the spinal cord microenvironment, we can better understand the underlying basis of recovery in MS and identify more targeted therapeutics, thus avoiding the current approach of systemic immunosuppression.

抽象的： 多发性硬化症（MS）是一种令人衰弱且复杂的自身免疫性疾病，其中髓鞘在其中 中枢神经系统受到攻击。复发的频率和严重程度高度可变，并链接到 环境和遗传病因。从MS的患者和动物模型获得的令人信服的数据 表明肠道微生物组是发病机理的关键介体。而 共生微生物群和免疫系统已经建立了良好 MS中看到的微生物群 - 免疫串扰尚不清楚。在这项拟议的研究中，我建议一个机械链接 在MS的小鼠模型中，微生物组和髓磷脂恢复之间，实验性自身免疫性脑脊髓炎 （eae）。一种称为芳基烃受体（AHR）的微生物代谢产物的传感器是转录因子 这可以调节在包括皮肤，肺部以及重要的是 胃肠道。 T细胞中的AHR活性具有修改肠道微生物组和修改的能力 免疫细胞适应性。以前的工作集中于种系AHR敲除或细胞特定敲除 神经系统；但是，我生产了一个CD4 T细胞特异性AHR基因敲除Mouseline，这些动物 表现出从EAE中依赖微生物组的恢复。这些小鼠初次均增加了髓磷脂的覆盖范围 疾病峰值处的脊髓中的瘫痪和IL-12降低。另外，我发现IL-12减少了 少突胶质细胞祖细胞（OPC）在体外分化为髓生成少突胶质细胞。在此 提案，我的目标是使用我先前描述的恢复模型T细胞AHR敲除小鼠，1）表征 透明病变中的髓磷脂动力学，2）确定IL-12作为中介的作用 免疫系统和髓生成少突胶质细胞祖细胞。我将确定髓磷脂是否恢复 是使用透射电子显微镜的OPC分化或成熟的少突胶质细胞恢复的结果 和谱系跟踪。我将尝试了解该模型中IL-12的来源和单元格的固有信号传导 IL-12影响的OPC和少突胶质细胞中的级联反应。最后，我将使用IL-12受体敲除 了解IL-12在体内髓鞘中的作用。了解这种机械的联系 微生物组和中枢神经系统将对早期阶段MS患者产生影响 复发症状。通过建立环境传感器（AHR）的直接和间接影响 脊髓微环境，我们可以更好地理解MS恢复的基本基础并确定 更具针对性的治疗剂，从而避免了当前的系统性免疫抑制方法。