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

• 批准号: 10659233
• 负责人: Carla M Cuda
• 金额: $ 78.96万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 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/10659233
• 关键词: Aging; Alzheimer' 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; Human; IFNAR1 gene; ITGAX gene; Immunology; Impaired cognition; In Vitro; Individual; Interferon Type I; Interferons; Investigation; Laboratories; Link; Literature; Macrophage; Macrophage Colony-Stimulating Factor Receptor; Mediator; 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; Research Personnel; 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; Universities; aged; antagonist; behavioral outcome; brain cell; chronic autoimmune disease; comorbidity; diagnostic strategy; effective therapy; experience; health related quality of life; immune cell infiltrate; improved; innovation; monocyte; mouse model; neuroimmunology; novel; novel therapeutics; peripheral blood; prevent; programs; receptor; single-cell RNA sequencing; synaptic pruning; systemic autoimmunity; targeted treatment; transcriptome sequencing

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 项目摘要 系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病， 导致多种有害合并症的因素。其中一种并发症是 称为中枢神经系统狼疮（NP-SLE）。尽管NP-SLE对健康相关的生活质量有影响， 尽管已经提出了多种机制，但没有一种机制可以单独解释NP-SLE的发病机制。我们发表了 脑内组织驻留巨噬细胞中NP-SLE特异性疾病标记的表达与 在出现明显的全身性疾病之前，两种NP-SLE模型中行为缺陷的严重程度。此外，我们的单细胞 RNA测序（scRNA-seq）数据识别组织驻留中的稳态和疾病相关状态 老年对照和NP-SLE易感小鼠的巨噬细胞。然而，疾病相关的巨噬细胞亚群 在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疾病相关转录程序的限制性表达 在NP-SLE组织驻留巨噬细胞对应于改善的行为结果在NP-SLE易感小鼠 在芬戈莫德治疗后。这些发现标志着第一次牵连这种疾病相关的组织- 在NP-SLE中，常驻巨噬细胞亚群作为潜在的致病群体，这与它们的 在文献中提出的保护作用。我们假设致病性疾病相关组织- 脑内的巨噬细胞对于NP-SLE的发展和靶向这一人群至关重要 可能代表治疗NP-SLE的新的治疗途径。在目标1中，我们将确定组织是否- NP-SLE需要常驻脑细胞或浸润性免疫细胞， WT和NP-SLE易感供体和受体的骨髓嵌合小鼠。我们将测试是否阻止过渡 通过缺失TREM 2（一种关键的功能调节因子）从体内平衡状态到疾病相关状态 在组织驻留的巨噬细胞中的（占该群体的10%）预防NP-SLE。我们将描述I型人格 干扰素（IFN）通过检查上游受体的作用在NP-SLE样疾病的发展中发挥作用 干扰素受体（IFNAR）和下游信号蛋白干扰素调节因子5（IRF 5），它们与SLE有关 易感性，通过删除这些信号介质在组织驻留的巨噬细胞。我们发现了一个 人脑脊液（CSF）中转录上类似于疾病相关组织驻留的亚群 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龛 我们在NP-SLE模型中看到了这些细胞的数值扩张。在目标2中，我们将获得配对CSF， 来自患有和不患有NP-SLE的SLE患者的外周血（PB）用于CSF的转录谱分析 巨噬细胞和PB单核细胞与临床结果相关。尽管调查了组织驻留 在其他学科中，我们将首先研究它们在NP-SLE中的作用。这些数据 将对下游开发改进的诊断或靶向治疗非常宝贵。