Role of the neurovascular molecule Wnt in regulating CNS inflammatory responses

神经血管分子Wnt在调节中枢神经系统炎症反应中的作用

• 批准号: 10668520
• 负责人: Igal Ifergan
• 金额: $ 40.5万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668520
• 关键词: Affect; Agonist; Animal Model; Anti-Inflammatory Agents; Antigen-Presenting Cells; Area; Astrocytes; Binding; Brain; Cell Nucleus; Cell Surface Receptors; Cell physiology; Cells; Central Nervous System; Chronic; Clinical; Dendritic Cells; Disease; Disease remission; Endothelial Cells; Environment; Equilibrium; Experimental Autoimmune Encephalomyelitis; Exposure to; Genes; Genetic Transcription; Glycogen Synthase Kinases; Goals; Human; Immune; Immune response; Immune system; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-12; Interleukin-6; Lesion; Ligands; Mediating; Multiple Sclerosis; Mus; Myelin; Myelogenous; Myeloid Cells; Pathologic; Pathway interactions; Peripheral Nervous System; Phosphorylation; Phosphotransferases; Play; Production; Relapse; Resolution; Role; Severities; Signal Transduction; Structure; T-Lymphocyte; Transcript; WNT Signaling Pathway; Wnt proteins; beta catenin; brain endothelial cell; cytokine; design; immunoregulation; in vivo; interleukin-23; monocyte; neuroinflammation; neuropathology; neurotoxic; neurovascular; neurovascular unit; programmed cell death ligand 1; remyelination; repaired; response

PROJECT SUMMARY/ABSTRACT The goal of our lab is to investigate immune regulation by innate cells for the treatment and resolution/repair of central nervous system (CNS) inflammatory diseases. During neuroinflammation the concerted actions of the CNS and the immune system affect the pathological responses mediated by infiltrating and resident immune cells. In particular, during multiple sclerosis (MS), myeloid cells are found in abundance within lesions. These myeloid antigen-presenting cells (APCs) have the ability to phagocytose myelin debris, release neurotoxic factors and promote the expansion and polarization of T cells in the CNS. However, they can also antagonize inflammation and promote repair. The exact mechanism(s) by which the CNS environment regulates myeloid APCs function during neuroinflammation remains ill defined. Analysis of the transcripts associated with MS-like lesions in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, revealed a significant enrichment of genes associated with the Wnt/b-catenin pathway as compared to non-lesioned areas. Binding of Wnt proteins to the cell surface receptor Frizzled (Fzd) inhibits glycogen synthase kinase 3b (GSK3b) and b-catenin phosphorylation, allowing b-catenin translocation to the nucleus and activates transcription of Wnt target genes. It has been demonstrated that Wnt signaling in dendritic cells (DCs) plays a central role in regulating the balance between inflammatory vs. regulatory responses in the gut. Blockade of GSK3b kinase was shown to increase IL-10 production by monocytes while suppressing the release of pro-inflammatory cytokines. In addition, our preliminary results demonstrate that following activation of the Wnt/b-catenin pathway, PD-L1 and PD-L2 expression were increased on human and mouse myeloid cells, while IL-1b, IL-6, IL-12 and IL-23 were reduced. Significantly, in EAE, Wnt agonist treatment decreased the clinical severity of chronic and relapsing-remitting EAE. Wnt proteins are naturally expressed in the CNS by brain endothelial cells (BBB-ECs) and astrocytes, and are upregulated during neuroinflammation. These cells make the neurovascular unit (NVU), a structure serving as an interface between the periphery and the CNS and hence directly exposed to the effects of peripheral and CNS driven inflammation. We hypothesize that inflammatory signals at the neurovascular level induce Wnt production by ECs and astroglial cells, which will regulate myeloid APCs function and promote anti- inflammatory responses that support repair and limit neuropathology. Using in vitro and in vivo approaches, our goal is to understand how Wnt ligands affect the immune response in the CNS and to determine the possibility to manipulate it in order to regulate myeloid cell function to reduce CNS-inflammatory responses and stimulate the repair mechanism.

项目摘要/摘要 我们实验室的目的是研究先天细胞的免疫调节，以治疗和解决/修复 中枢神经系统（CNS）炎症性疾病。在神经炎症期间 中枢神经系统和免疫系统会影响浸润和居民免疫介导的病理反应 细胞。特别是，在多发性硬化症（MS）期间，髓样细胞在病变中大量发现。这些 髓样抗原呈递细胞（APC）具有吞噬髓磷脂碎片的能力，释放神经毒性因子 并促进中枢神经系统中T细胞的扩张和极化。但是，它们也可以对抗 炎症并促进修复。 CNS环境调节髓样的确切机制 神经炎症期间的APC功能仍未定义。 分析与实验性自身免疫性脑脊髓炎（EAE）中与MS样病变相关的转录本， MS的动物模型揭示了与Wnt/B-catenin途径相关的基因的显着富集 与非仪器区域相比。 Wnt蛋白与细胞表面受体的结合被抑制（FZD） 糖原合酶激酶3B（GSK3B）和B-catenin磷酸化，允许B-catenin易位 细胞核和激活Wnt靶基因的转录。已经证明了树突状的Wnt信号传导 细胞（DC）在调节炎症与调节反应之间的平衡方面起着核心作用 肠。显示GSK3B激酶的阻断可通过单核细胞增加IL-10的产生，同时抑制 促炎细胞因子的释放。此外，我们的初步结果表明，激活后 在人和小鼠髓样细胞上增加了Wnt/b-catenin途径，PD-L1和PD-L2表达， 而IL-1B，IL-6，IL-12和IL-23降低。值得注意的是，在EAE中，Wnt激动剂治疗降低了 慢性和复发的EAE的临床严重程度。 Wnt蛋白自然在中枢神经系统中由脑内皮细胞（BBB-EC）和星形胶质细胞表达，并且是 神经炎症期间上调。这些细胞使神经血管单元（NVU）成为一种结构 外围与中枢神经系统之间的界面，因此直接暴露于外围和 中枢神经系统驱动炎症。我们假设神经血管水平的炎症信号会诱导Wnt EC和星形胶质细胞的生产，该细胞将调节髓样APC的功能并促进抗 - 支持修复并限制神经病理学的炎症反应。使用体外和体内 方法是，我们的目标是了解Wnt配体如何影响中枢神经系统的免疫反应并确定 操纵它以调节髓样细胞功能以减少CNS炎症反应的可能性 并刺激修复机制。