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.

抽象的系统性红斑狼疮是一种无法治愈的自身免疫性疾病，其特征是致病性自身抗体会加剧皮肤、肺和肾脏等组织的炎症损伤。狼疮患者还会出现从严重头痛、癫痫发作到神经精神病等神经系统症状统称为中枢神经系统狼疮。我们认为神经系统症状是由周围神经系统引起的干扰素α进入大脑并激活小胶质细胞和补体依赖性修剪途径导致涉及认知、空间记忆和社会行为的大脑区域突触丢失。研究于狼疮小鼠模型表明外周免疫细胞和自身抗体可能穿透血脑屏障并诱发病理。然而，狼疮患者经常会发现神经精神病症状疾病早期表明其他因素可能参与损伤而不破坏血脑障碍。在我们自己使用狼疮小鼠模型的研究中，初步结果确定了年龄依赖性激活小胶质细胞的频率显着增加，这些神经胶质细胞对神经元突触的摄取呈阳性材料。值得注意的是，狼疮小鼠的行为发生了与突触损失相关的变化。这小胶质细胞激活和突触修剪的模式与早期神经发育过程中观察到的相似选择性突触消除是正常的。值得注意的是，用抗干扰素对狼疮小鼠进行体内治疗受体抗体具有保护作用。该提案的目的是检验我们的假设，即外围 I 型干扰素等细胞因子会触发小胶质细胞依赖性突触修剪程序，从而导致突触消除的增加可以解释狼疮中观察到的神经系统症状。这提出以下两个目标。具体目标 1：检验小胶质细胞介导的突触修剪在以下情况下被激活的假设：系统性红斑狼疮。根据我们的初步数据，我们预测 SLE 小鼠中会发生小胶质细胞依赖性突触丢失模型，并且该过程需要经典补体级联的激活。具体目标 2：检验 SLE 中 I 型干扰素信号传导增加促进 CNS 的假设我们预测 I 型干扰素刺激的小胶质细胞会激活突触修剪基因程序导致神经元物质的不当吞噬以及认知和社会功能障碍的发展。此外，初步结果表明，抗 IFNAR 治疗可能具有保护作用并防止突触损失。