Type I interferon-dependent mechanisms of synapse loss in lupus
狼疮突触丢失的 I 型干扰素依赖性机制
基本信息
- 批准号:10433932
- 负责人:
- 金额:$ 46.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-16 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAlzheimer&aposs DiseaseAnxietyAutoantibodiesAutoimmune DiseasesBehaviorBloodBlood - brain barrier anatomyBrainBrain regionCellsCentral Nervous System DiseasesCerebrospinal FluidCognitionComplementComplement component C4aDataDefectDevelopmentDiseaseFc ReceptorFrequenciesFunctional disorderGene ExpressionGenesHeadacheHigh PrevalenceIFNAR1 geneImmuneImpaired cognitionInflammationInflammatoryInjuryInterferon ReceptorInterferon Type IInterferon-alphaInterferonsKidneyKnowledgeLeadLinkLungLupusMediatingMental DepressionMicrogliaMicrovascular DysfunctionModelingMusNeurologicNeurologic SymptomsNeuronsNeuropsychiatric Systemic Lupus ErythematosusPathogenicityPathologyPathway interactionsPatientsPatternPeripheralPhagocytesPhagocytosisPredispositionProcessProductionPsychosesPublishingRecombinantsSchizophreniaSeizuresSerumSignal TransductionSkinSocial BehaviorSourceSymptomsSynapsesSystemic Lupus ErythematosusTestingTissuesVariantage relatedautoreactive B cellbasebehavioral phenotypingblood-brain barrier permeabilizationbrain endothelial cellcognitive developmentcommon symptomcytokinedensityexperiencefrontal lobegray matterin vivointerferon alpha receptorlupus prone micemacrophagemouse modelneurodevelopmentneuron lossnoveloverexpressionpathogenic autoantibodiespreventprogramsreceptorrelating to nervous systemresponsesocial deficitsspatial memorysynaptic pruninguptake
项目摘要
Abstract
Systemic lupus erythematosus is an incurable autoimmune disease characterized by pathogenic
autoantibodies that potentiate inflammatory injury in tissues such as skin, lungs and kidneys. Lupus patients
also experience neurologic symptoms that range from severe headache and seizures to neuropsychosis and
are collectively referred to as CNS Lupus. We propose that neurologic symtoms result from peripheral
interferon alpha that enters the brain and activates the microglia and complement -dependent pruning pathway
leading to synapse loss in brain regions involved in cognition, spatial memory and social behavior. Studies in
murine models of lupus suggest that peripheral immune cells and autoantibody may penetrate the blood brain
barrier and induce pathology. However, in lupus patients symptoms of neuropsychosis are often detected
early in disease suggesting that other factors might be involved in injury without destruction of the blood brain
barrier. In our own study using a murine model of lupus, preliminary results identify an age-dependent
significant increase in the frequency of activated microglia that are positive for uptake of neuronal synaptic
material. Remarkably, the lupus mice develop changes in behavior that correlate with synapse loss. The
pattern of microglia activation and synaptic pruning is similar to that observed during early neural development
where selective synapse elimination is normal. Notably, treatment of the lupus mice in vivo with anti-interferon
receptor antibody was protective. The objective of this proposal is to test our hypothesis that peripheral
cytokines such as type I interferon trigger a microglia-dependent synaptic pruning program leading to
increased elimination of synapses that could explain the neurological symptoms observed in lupus. The
following two aims are proposed.
Specific aim 1: Test the hypothesis that microglia-mediated synaptic pruning becomes activated in
SLE. Based on our preliminary data, we predict that microglia-dependent synapse loss occurs in SLE mouse
models and that activation of the classical complement cascade is required for this process.
Specific aim 2: Test the hypothesis that increased type I interferon signaling in SLE promotes CNS
dysfunction We predict that type I interferon-stimulated microglia activate a synapse pruning gene program
leading to inappropriate engulfment of neuronal material and development of cognitive and social dysfunction.
Moreover, preliminary results suggest that treatment with anti-IFNAR may be protective and prevent synapse
loss.
摘要
系统性红斑狼疮是一种不可治愈的自身免疫性疾病,其特点是
自身抗体会加重皮肤、肺和肾脏等组织的炎症性损伤。狼疮患者
也有神经症状,从严重的头痛和癫痫到神经精神病和
统称为CNS狼疮。我们认为神经系统症状是由外周引起的。
进入大脑并激活小胶质细胞和补体依赖的修剪途径的干扰素
导致涉及认知、空间记忆和社会行为的大脑区域的突触丢失。研究项目:
狼疮小鼠模型提示外周免疫细胞和自身抗体可能穿透血脑
屏障和诱导病理。然而,在狼疮患者中,经常会检测到神经精神病的症状。
在疾病的早期,表明其他因素可能参与了损伤而不破坏血脑
障碍。在我们自己使用狼疮小鼠模型进行的研究中,初步结果确定了年龄相关性
神经突触摄取阳性的激活小胶质细胞的频率显著增加
材料。值得注意的是,狼疮小鼠的行为发生了与突触丢失相关的变化。这个
小胶质细胞激活和突触修剪的模式与早期神经发育时观察到的相似
选择性突触消除是正常的。值得注意的是,用抗干扰素在体内治疗狼疮小鼠
受体抗体具有保护性作用。这项提议目的是检验我们的假设
I型干扰素等细胞因子触发小胶质细胞依赖的突触修剪程序,导致
突触清除增加,这可以解释狼疮的神经症状。这个
提出了以下两个目标。
具体目标1:测试小胶质细胞介导的突触修剪在脑内激活的假设
SLE。根据我们的初步数据,我们预测在SLE小鼠中会发生小胶质细胞依赖性突触丢失
模型和经典补体级联的激活是这一过程所必需的。
特定目标2:验证SLE中I型干扰素信号增加促进中枢神经系统的假设
功能障碍我们预测I型干扰素刺激的小胶质细胞激活突触修剪基因程序
导致神经元物质不适当地被吞噬,并发展为认知和社会功能障碍。
此外,初步结果表明,用抗IFNAR治疗可能具有保护和防止突触的作用
损失。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Microglial responses to peripheral type 1 interferon.
- DOI:10.1186/s12974-020-02003-z
- 发表时间:2020-11-12
- 期刊:
- 影响因子:9.3
- 作者:Aw E;Zhang Y;Carroll M
- 通讯作者:Carroll M
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Michael Craig Carroll其他文献
Michael Craig Carroll的其他文献
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{{ truncateString('Michael Craig Carroll', 18)}}的其他基金
Astrocyte-neuron communication and vulnerability to mental illness
星形胶质细胞-神经元通讯和患精神疾病的脆弱性
- 批准号:
10686440 - 财政年份:2022
- 资助金额:
$ 46.17万 - 项目类别:
Neuroimmune mechanisms of adolescent brain development and vulnerability
青少年大脑发育和脆弱性的神经免疫机制
- 批准号:
10686442 - 财政年份:2022
- 资助金额:
$ 46.17万 - 项目类别:
Contributions of human C4A overexpression to schizophrenia pathogenesis.
人类 C4A 过度表达对精神分裂症发病机制的贡献。
- 批准号:
10686441 - 财政年份:2022
- 资助金额:
$ 46.17万 - 项目类别:
Evolution of autoreactive GC and epitope spreading in lupus
狼疮自身反应性GC和表位扩散的演变
- 批准号:
10736511 - 财政年份:2018
- 资助金额:
$ 46.17万 - 项目类别:
Evolution of autoreactive GC and epitope spreading in lupus
狼疮自身反应性GC和表位扩散的演变
- 批准号:
10399632 - 财政年份:2018
- 资助金额:
$ 46.17万 - 项目类别:
Type I interferon-dependent mechanisms of synapse loss in lupus
狼疮突触丢失的 I 型干扰素依赖性机制
- 批准号:
10196940 - 财政年份:2018
- 资助金额:
$ 46.17万 - 项目类别:
Astrocyte-neuron communication and vulnerability to mental illness
星形胶质细胞-神经元通讯和患精神疾病的脆弱性
- 批准号:
10693115 - 财政年份:2017
- 资助金额:
$ 46.17万 - 项目类别:
Contributions of human C4A overexpression to schizophrenia pathogenesis.
人类 C4A 过度表达对精神分裂症发病机制的贡献。
- 批准号:
10693119 - 财政年份:2017
- 资助金额:
$ 46.17万 - 项目类别: