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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无法治愈的自身免疫性疾病，自身抗体增强组织如皮肤、肺和肾中的炎性损伤。狼疮患者也经历从严重头痛和癫痫到神经精神病的神经症状，统称为CNS狼疮。我们认为，神经症状的结果，从外周干扰素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大脑中涉及认知、空间记忆和社会行为的区域的突触丢失。研究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和诱发病理。然而，在狼疮患者的神经精神病的症状往往是检测这表明其他因素可能参与损伤而不破坏血脑屏障在我们自己使用狼疮小鼠模型的研究中，初步结果表明，神经元突触摄取阳性的活化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。的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，用抗干扰素在体内治疗狼疮小鼠受体抗体具有保护作用。这项提议的目的是检验我们的假设，细胞因子如I型干扰素触发小胶质细胞依赖性突触修剪程序，突触的消除增加，这可以解释在狼疮中观察到的神经症状。的提出了以下两个目标。具体目标1：检验小胶质细胞介导的突触修剪在神经元内被激活的假设。 SLE。基于我们的初步数据，我们预测SLE小鼠中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需要这个过程。具体目的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型干扰素刺激小胶质细胞激活突触修剪基因程序导致神经元物质的不适当吞噬和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，损失