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

西北大学 项目总结 系统性红斑狼疮(SLE)是一种涉及遗传和环境因素的慢性自身免疫性疾病 最终导致多种有害共病的因素。一种这样的共病是所涉及的 TO AS CNS狼疮(NP-SLE)。尽管NP-SLE对与健康相关的生活质量有影响，尽管 机制已被提出，没有一个能单独解释NP-SLE的发病机制。我们发表了那篇文章 脑内组织驻留巨噬细胞中NP-SLE特异性疾病标志物的表达与 两种NP-SLE模型在显性系统性疾病前行为缺陷的严重程度。此外，我们的单细胞 Rna测序(scrna-seq)数据识别组织驻留的体内平衡状态和疾病相关状态。 老年对照组和NP-SLE倾向小鼠的巨噬细胞。然而，与疾病相关的巨噬细胞亚群 在NP-SLE中，与吞噬功能相关的基因缺失，这与其已知的吞噬功能相反 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中，组织驻留的巨噬细胞对应于NP-SLE倾向小鼠行为结果的改善 在使用Fingolimod治疗后。这些发现标志着第一次将这种与疾病相关的组织- 作为NP-SLE潜在致病群体的常驻巨噬细胞亚群与其 在文献中提出了保护作用。我们假设致病相关组织- 脑内驻留的巨噬细胞对NP-SLE的发生和目标人群至关重要。 可能为治疗NP-SLE开辟新的治疗途径。在目标1中，我们将确定组织是否- NP-SLE需要驻留的脑细胞或渗入的免疫细胞，使用相互的头屏蔽骨 WT和NP-SLE倾向供受者的骨髓嵌合小鼠。我们将测试是否阻止过渡 通过缺失TREM2(一种关键的功能调节因子)从动态平衡状态到疾病相关状态 在组织驻留的巨噬细胞中)可预防NP-SLE。我们将描述类型I的角色 干扰素通过检测上游受体在NP-SLE样疾病的发生发展中的作用 (IFNAR)和下游信号蛋白干扰素调节因子5(IRF5)，已被认为与SLE有关 易感性，通过删除这些驻留在组织中的巨噬细胞中的信号媒介。我们确认了一个细胞 人类脑脊液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。 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，我们将获得配对的脑脊液和 系统性红斑狼疮伴与不伴NP-SLE患者外周血脑脊液转录谱分析 巨噬细胞和外周血单核细胞与临床结局相关。尽管对组织居住者进行了调查 巨噬细胞在大脑中的其他学科，我们将第一次检查它们在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是无价的。

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.