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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