Defining signals contributing to inflammatory hemophagocyte differentiation in TLR7 mediated Macrophage Activation Syndrome

定义 TLR7 介导的巨噬细胞激活综合征中炎症噬血细胞分化的信号

• 批准号: 10534552
• 负责人: Natalie K Thulin
• 金额: $ 4.3万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2025-09-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10534552
• 关键词: ATAC-seq; Ablation; Acute; Address; Agonist; Anemia; Automobile Driving; Cessation of life; Characteristics; Chronic; Complication; Data; Development; Disease; Dose; Education; Emergency Situation; Erythrocytes; Faculty; Family; Genes; Genetic Predisposition to Disease; Goals; Heme; Human; Immunosuppression; In Vitro; Infection; Inflammation; Inflammatory; Innate Immune Response; Institution; Interferon Type I; Interferons; Intermittent Pyrexia; Light; Macrophage activation syndrome; Mediating; Modeling; Multiple Organ Failure; Mus; Myelopoiesis; Natural Immunity; Patients; Phagocytes; Phagocytosis; Phenotype; Population; Production; RNA; Red Blood Cell Count; Research; Research Personnel; Rheumatism; Role; Signal Transduction; Symptoms; Systemic Lupus Erythematosus; TLR7 gene; Thrombocytopenia; Training; Virus Diseases; Work; base; cytokine; cytokine release syndrome; cytopenia; effective therapy; experimental study; familial hemophagocytic lymphohistiocytosis; human disease; in vitro Assay; in vivo; inducible gene expression; insight; macrophage; member; model development; monocyte; mouse model; novel; overexpression; receptor; sensor; systemic juvenile idiopathic arthritis; transcription factor; transcriptome sequencing

Project Summary/Abstract The goal of this research is to investigate the development of inflammatory macrophages and disease in Macrophage Activation Syndrome (MAS). MAS is a serious and potentially fatal complication of rheumatic disease or viral infection. MAS is characterized by the development of cytopenias, including anemia and thromobocytopenia, and accumulation of hemophagocytes— activated macrophages that phagocytose red blood cells (RBCs). I will investigate spontaneous MAS-like disease in a mouse model of Systemic Lupus Erythematosus. In the TLR7.1 model, the overexpression of and constitutively active signaling through the endosomal single-stranded RNA sensor Toll-like receptor 7 (TLR7) drives chronic inflammation and subsequent MAS disease. TLR7.1 mice develop thrombocytopenia, anemia, and a novel population of hemophagocytes, inflammatory hemophagocytes (iHPCs), that spontaneously differentiate from Ly6Chi monocytes. Further, in this model, the development of anemia is positively correlated with iHPC phagocytosis of RBCs indicating that iHPC activity may be driving disease. In humans, SNPs in the gene encoding the transcription factor interferon regulatory factor 5 (IRF5) are associated with MAS development. IRF5 signaling is critical for the development of inflammatory macrophages in the context several inflammatory diseases. Previous work in our lab showed that IRF5 ablation in vivo ameliorates iHPC differentiation downstream of acute TLR7 signaling. However, in the context of in vivo TLR7- driven MAS, the role of IRF5 signaling in iHPC production and in MAS disease is unclear. In preliminary data, I show in TLR7.1 mice that signaling through IRF5 is critical for iHPC development, iHPC RBC phagocytosis, and anemia and thrombocytopenia indicative of MAS disease development. Based on these findings, the goal of my proposal is to determine the role of IRF5 signaling, specifically in Ly6Chi monocytes, in TLR7- driven iHPC differentiation and MAS disease (AIM 1), and to determine what other signals synergize with TLR7 to drive iHPC differentiation and MAS disease, with a specific focus on heme and type I interferons (AIM 2). Overall, completion of the proposed research along with my additional training described here will allow me to pursue my goals of becoming an independent investigator and faculty member with a focus on education.

项目总结/摘要 这项研究的目的是调查炎症巨噬细胞和疾病的发展， 巨噬细胞活化综合征（MAS）。MAS是风湿性关节炎的一种严重且可能致命的并发症， 疾病或病毒感染。MAS的特征在于发生血细胞减少，包括贫血和 血小板减少和吞噬红细胞的噬血细胞激活的巨噬细胞蓄积 血细胞（RBC）。我将在系统性狼疮小鼠模型中研究自发性MAS样疾病 红斑。在TLR7.1模型中，TLR7.1的过表达和通过TLR7.1的组成型活性信号传导被抑制。 内体单链RNA传感器Toll样受体7（TLR7）驱动慢性炎症和随后的炎症反应。 MAS病。TLR7.1小鼠发生血小板减少症、贫血和新的噬血细胞群体， 炎性噬血细胞（iHPC），其自发地从Ly6Chi单核细胞分化。此外，在此 模型中，贫血的发生与iHPC对RBC的吞噬作用呈正相关，表明iHPC 活动可能会导致疾病。 在人类中，编码转录因子干扰素调节因子5（IRF5）的基因中的SNP是 与MAS的发展有关。IRF5信号传导对炎症巨噬细胞的发展至关重要 在几种炎症性疾病的背景下。我们实验室先前的工作表明，体内IRF5消融 改善急性TLR 7信号传导下游的iHPC分化。然而，在体内TLR7- 在iHPC驱动的MAS中，IRF5信号传导在iHPC产生和MAS疾病中的作用尚不清楚。根据初步数据，我 在TLR7.1小鼠中显示，通过IRF5的信号传导对于iHPC发育、iHPC RBC吞噬作用和 提示MAS疾病发展的贫血和血小板减少症。根据这些发现，我的目标是 一个建议是确定IRF5信号传导的作用，特别是在Ly6Chi单核细胞中，在TLR7驱动的iHPC中 分化和MAS疾病（AIM 1），并确定哪些其他信号与TLR7协同作用以驱动iHPC 分化和MAS疾病，特别关注血红素和I型干扰素（AIM 2）。总体而言， 拟议的研究沿着以及我在这里描述的额外培训将使我能够追求我的目标， 成为一名独立的调查员和教师，专注于教育。