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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：
Michael Craig Carroll
金额：
$ 46.17万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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：
https://reporter.nih.gov/project-details/10433932
关键词：
Affect Alzheimer&apos s Disease Anxiety Autoantibodies Autoimmune Diseases Behavior Blood Blood - brain barrier anatomy Brain Brain region Cells Central Nervous System Diseases Cerebrospinal Fluid Cognition Complement Complement component C4a Data Defect Development Disease Fc Receptor Frequencies Functional disorder Gene Expression Genes Headache High Prevalence IFNAR1 gene Immune Impaired cognition Inflammation Inflammatory Injury Interferon Receptor Interferon Type I Interferon-alpha Interferons Kidney Knowledge Lead Link Lung Lupus Mediating Mental Depression Microglia Microvascular Dysfunction Modeling Mus Neurologic Neurologic Symptoms Neurons Neuropsychiatric Systemic Lupus Erythematosus Pathogenicity Pathology Pathway interactions Patients Pattern Peripheral Phagocytes Phagocytosis Predisposition Process Production Psychoses Publishing Recombinants Schizophrenia Seizures Serum Signal Transduction Skin Social Behavior Source Symptoms Synapses Systemic Lupus Erythematosus Testing Tissues Variant age related autoreactive B cell base behavioral phenotyping blood-brain barrier permeabilization brain endothelial cell cognitive development common symptom cytokine density experience frontal lobe gray matter in vivo interferon alpha receptor lupus prone mice macrophage mouse model neurodevelopment neuron loss novel overexpression pathogenic autoantibodies prevent programs receptor relating to nervous system response social deficits spatial memory synaptic pruning uptake

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。