The Relationship Between Brain Macrophages and Cognitive Dysfunction in Systemic Lupus Erythematosus

系统性红斑狼疮脑巨噬细胞与认知功能障碍的关系

基本信息

批准号：
10504828
负责人：
Carla M Cuda
金额：
$ 79.9万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2022-07-05 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10504828
关键词：
Aging Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Autopsy Behavior Behavioral Biometry Biopsy Blood Bone Marrow Brain CASP8 gene Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cerebrospinal Fluid Clinical Data Defect Development Diagnosis Diagnostic Diagnostic tests Discipline Disease Disease associated microglia Disease remission Environmental Risk Factor Ethics Exhibits Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Transcription Head Heterogeneity Hippocampus (Brain)Human IFNAR1 gene ITGAX gene Immunology Impaired cognition In Vitro Individual Interferon Type I Interferons Investigation Laboratories Link Literature Macrophage Colony-Stimulating Factor Receptor Mediator of activation protein Microglia Modeling Molecular Mus Neuropsychiatric Systemic Lupus Erythematosus Outcome PTPRC gene Pathogenesis Pathogenicity Pathology Pathway interactions Patient-Focused Outcomes Patients Phagocytes Phagocytosis Play Population Predisposition Publications Publishing Quality of life Receptor Signaling Research Role Sampling Severities Signal Transduction Signaling Protein Sphingosine-1-Phosphate Receptor Systemic Lupus Erythematosus Systemic disease TREM2 gene Target Populations Testing Time Tissues Transcend Treatment Side Effects Tumor-infiltrating immune cells Universities aged antagonist behavioral outcome brain cell chronic autoimmune disease comorbidity diagnostic strategy effective therapy experience health related quality of life improved innovation macrophage monocyte mouse model neuroimmunology novel novel therapeutics peripheral blood prevent programs receptor single-cell RNA sequencing synaptic pruning systemic autoimmunity targeted treatment transcriptome sequencing

项目摘要

Northwestern University PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving genetic and environmental factors culminating in multiple detrimental comorbidities. One such comorbidity is the onset of what is referred to as CNS lupus (NP-SLE). Despite the impact of NP-SLE on health-related quality of life and although numerous mechanisms have been proposed, none can solely account for NP-SLE pathogenesis. We published that expression of NP-SLE-specific disease signatures in tissue-resident macrophages in the brain correlates with the severity of behavioral deficits in two NP-SLE models prior to overt systemic disease. Further, our single-cell RNA sequencing (scRNA-seq) data identify homeostatic and disease-associated states in tissue-resident macrophages of aged control and NP-SLE-prone mice. However, the disease-associated macrophage subset in NP-SLE is depleted for genes associated with phagocytosis, which is in contrast to their known phagocytic role in other diseases. We also find that restricted expression of the disease-associated transcriptional program in NP-SLE tissue-resident macrophages corresponds to improved behavioral outcomes in NP-SLE-prone mice following treatment with fingolimod. These discoveries mark the first to implicate this disease-associated tissue- resident macrophage subset as a potentially pathogenic population in NP-SLE, which contrasts with their proposed protective role in the literature. We hypothesize that pathogenic disease-associated tissue- resident macrophages in the brain are crucial for NP-SLE development and targeting this population may represent a new therapeutic avenue for treating NP-SLE. In Aim 1, we will determine whether tissue- resident brain cells or infiltrating immune cells are required for NP-SLE using reciprocal head-shielded bone marrow chimeric mice of WT and NP-SLE-prone donors and recipients. We will test whether blocking transition from the homeostatic state to the disease-associated state via deletion of TREM2 (a critical functional regulator of this population) in tissue-resident macrophages prevents NP-SLE. We will delineate the role that type I interferon (IFN) plays in the development of NP-SLE-like disease by examining the role for the upstream receptor (IFNAR) and downstream signaling protein IFN regulatory factor 5 (IRF5), which have been linked to SLE susceptibility, via deletion of these signaling mediators in tissue-resident macrophages. We identified a cell subset in human cerebrospinal fluid (CSF) that transcriptionally resembles disease-associated tissue-resident macrophages. Moreover, classical monocytes can repopulate a compromised tissue-resident macrophage niche and we see numerical expansion of these cells in NP-SLE models. In Aim 2, we will obtain paired CSF and peripheral blood (PB) from SLE patients with and without NP-SLE for transcriptional profiling of CSF macrophages and PB monocytes to correlate with clinical outcomes. Despite investigation of tissue-resident macrophages in the brain in other disciplines, we will be the first to examine their role in NP-SLE. These data will be invaluable for downstream development of improved diagnostics or targeted therapies.

西北大学项目概要系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，涉及遗传和环境因素最终导致多种有害合并症的因素。其中一种合并症是所提到的疾病的发作中枢神经系统狼疮 (NP-SLE)。尽管 NP-SLE 对健康相关的生活质量有影响，并且尽管有许多虽然已经提出了一些机制，但没有一个可以单独解释 NP-SLE 的发病机制。我们发表了大脑组织驻留巨噬细胞中 NP-SLE 特异性疾病特征的表达与两个 NP-SLE 模型在明显的全身性疾病之前行为缺陷的严重程度。此外，我们的单细胞 RNA 测序 (scRNA-seq) 数据可识别组织驻留体内的稳态和疾病相关状态衰老对照小鼠和易患 NP-SLE 小鼠的巨噬细胞。然而，与疾病相关的巨噬细胞亚群 NP-SLE 中与吞噬作用相关的基因被耗尽，这与它们已知的吞噬作用相反在其他疾病中的作用。我们还发现与疾病相关的转录程序的限制表达 NP-SLE 组织驻留巨噬细胞中的 NP-SLE 与易患 NP-SLE 小鼠的行为结果改善相对应使用芬戈莫德治疗后。这些发现标志着第一个涉及这种疾病相关组织的发现常驻巨噬细胞亚群作为 NP-SLE 中的潜在致病群体，这与其文献中提出的保护作用。我们假设与致病性疾病相关的组织大脑中常驻的巨噬细胞对于 NP-SLE 的发展和针对该人群至关重要可能代表治疗 NP-SLE 的新治疗途径。在目标 1 中，我们将确定组织是否- 使用交互头部屏蔽骨的 NP-SLE 需要常驻脑细胞或浸润免疫细胞 WT 和 NP-SLE 易感供体和受体的骨髓嵌合小鼠。我们将测试是否阻塞转换通过删除 TREM2（一种关键的功能调节因子）从稳态到疾病相关状态组织驻留巨噬细胞中的该人群的人）可预防 NP-SLE。我们将描述 I 类角色通过检查上游受体的作用，干扰素 (IFN) 在 NP-SLE 样疾病的发展中发挥作用 (IFNAR) 和下游信号蛋白 IFN 调节因子 5 (IRF5)，与 SLE 相关通过删除组织驻留巨噬细胞中的这些信号传导介质来提高易感性。我们识别出一个细胞人类脑脊液 (CSF) 中的子集，其转录类似于疾病相关组织驻留巨噬细胞。此外，经典单核细胞可以重新填充受损的组织驻留巨噬细胞生态位我们在 NP-SLE 模型中看到这些细胞的数值扩展。在目标 2 中，我们将获得配对的 CSF 和患有或不患有 NP-SLE 的 SLE 患者的外周血 (PB)，用于 CSF 转录谱分析巨噬细胞和 PB 单核细胞与临床结果相关。尽管对组织驻留进行了调查在其他学科中，我们将首先研究大脑中的巨噬细胞在 NP-SLE 中的作用。这些数据对于改进诊断或靶向治疗的下游开发将具有无价的价值。