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
基本信息
- 批准号:10798521
- 负责人:
- 金额:$ 25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffectAgonistAnimal ModelAnti-Inflammatory AgentsAntigen-Presenting CellsAreaAstrocytesBindingBrainCell NucleusCell Surface ReceptorsCell physiologyCellsCentral Nervous SystemChronicClinicalDendritic CellsDiseaseDisease remissionEndothelial CellsEnvironmentEquilibriumExperimental Autoimmune EncephalomyelitisExposure toGenesGenetic TranscriptionGlycogen Synthase KinasesGoalsHumanImmuneImmune responseImmune systemIn VitroInfiltrationInflammationInflammatoryInflammatory ResponseInterleukin-10Interleukin-12Interleukin-6LesionLigandsMediatingMultiple SclerosisMusMyelinMyelogenousMyeloid CellsPathologicPathway interactionsPeripheral Nervous SystemPhosphorylationPhosphotransferasesPlayProductionRelapseResolutionRoleSeveritiesSignal TransductionStructureT-LymphocyteTranscriptWNT Signaling PathwayWnt proteinsbeta cateninbrain endothelial cellcytokinedesignimmunoregulationin vivointerleukin-23monocyteneuroinflammationneuropathologyneurotoxicneurovascularneurovascular unitprogrammed cell death ligand 1remyelinationrepairedresponse
项目摘要
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
我们实验室的目标是研究天然细胞的免疫调节作用,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影响浸润性免疫和常驻免疫介导的病理反应
细胞。特别是,在多发性硬化症(MS)期间,病变内发现大量的髓系细胞。这些
髓系抗原提呈细胞(APC)具有吞噬髓鞘碎片、释放神经毒性因子的能力
促进中枢神经系统T细胞的扩增和极化。然而,他们也可能会产生敌意
发炎,促进修复。中枢神经系统环境调节髓系细胞的确切机制(S)
APC在神经炎症过程中的作用仍不清楚。
实验性自身免疫性脑脊髓炎MS样病变相关转录本分析,
多发性硬化症的动物模型显示与Wnt/b-连环蛋白途径相关的基因显著丰富
与非皮损区域相比。Wnt蛋白与细胞表面受体FrizzledFZD的结合抑制作用
糖原合成酶3b(GSK3b)和b-连环蛋白的磷酸化,使b-连环蛋白易位到
并激活Wnt靶基因的转录。已证实Wnt信号在树突状细胞中的表达
树突状细胞(DC)在调节炎症反应与调节反应之间的平衡中起着核心作用
直觉。阻断GSK3b激酶可增加单核细胞产生IL-10,同时抑制
释放促炎细胞因子。此外,我们的初步结果表明,以下激活
在Wnt/b-catenin通路中,PD-L1和PD-L2在人和小鼠髓系细胞上的表达增加,
IL-1b、IL-6、IL-12、IL-23降低。值得注意的是,在EAE中,Wnt激动剂治疗降低了
慢性和复发缓解型EAE的临床严重性。
WNT蛋白在中枢神经系统中由脑内皮细胞(BBB-ECs)和星形胶质细胞自然表达,并且
在神经炎症期间表达上调。这些细胞形成神经血管单位(NVU),这是一种充当
外围设备和中枢神经系统之间的接口,因此直接暴露于外围设备和
中枢神经系统导致炎症。我们假设神经血管水平的炎症信号诱导WNT
由内皮细胞和星形胶质细胞产生,它将调节髓系APC的功能,并促进抗
支持修复和限制神经病理的炎症反应。在体外和体内使用
方法,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
操纵它以调节髓系细胞功能以减少中枢神经系统炎症反应的可能性
并激发修复机制。
项目成果
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{{ truncateString('Igal Ifergan', 18)}}的其他基金
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 - 财政年份:2022
- 资助金额:
$ 25万 - 项目类别:
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