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.

摘要： 多发性硬化症（MS）是一种使人衰弱的复杂的自身免疫性疾病，其中多发性硬化症（MS）中的髓磷脂（myelin）是一种免疫性疾病。 中枢神经系统受到攻击。复发的频率和严重程度差异很大，并且与以下因素有关 包括环境和遗传病因。从MS患者和动物模型中获得的令人信服的数据 表明肠道微生物组是发病机制的关键介质。虽然， 肠道微生物群和免疫系统已经很好地建立起来， 在MS中观察到的微生物群免疫串扰仍不清楚。在这项研究中，我提出了一个机械的联系， MS小鼠模型中微生物组和髓鞘恢复之间的关系，实验性自身免疫性脑脊髓炎 （EAE）。微生物代谢物的传感器称为芳香烃受体（AHR）是一种转录因子 调节屏障组织（包括皮肤、肺）的免疫和代谢稳态，重要的是， 胃肠道T细胞中的AHR活性具有改变肠道微生物组以及改变肠道微生物组的能力。 免疫细胞适应性以前的工作集中在生殖系AHR敲除或细胞特异性敲除， 然而，我已经产生了CD4 T细胞特异性AHR敲除小鼠，这些动物 表现出从EAE的微生物组依赖性恢复。这些小鼠在最初的治疗后增加了髓鞘覆盖率。 瘫痪和疾病高峰时脊髓中的IL-12减少。此外，我发现IL-12降低了 寡突胶质细胞祖细胞（OPC）在体外分化为髓鞘形成的寡突胶质细胞。根据本 根据我的建议，我的目标是使用我以前描述的恢复模型，T细胞Ahr敲除小鼠，以1）表征 髓鞘再生损伤中的髓鞘动力学和2）确定IL-12作为中间体的作用， 免疫系统和髓鞘生成少突胶质细胞祖细胞。我会确定髓磷脂的恢复 是OPC分化的结果或使用透射电子显微镜观察成熟少突胶质细胞恢复的结果 和血统追踪我将试图了解IL-12在这个模型中的来源和细胞内在信号传导 受IL-12影响的OPCs和少突胶质细胞中的级联。最后，我将利用IL-12受体敲除， 了解IL-12在体内髓鞘形成过程中的作用。理解这种机械的联系， 微生物组和中枢神经系统将对早期MS患者从 复发症状通过建立环境传感器（AHR）对环境的直接和间接影响， 脊髓微环境，我们可以更好地了解MS恢复的基础， 更有针对性的治疗，从而避免了目前的全身免疫抑制方法。