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: 10759369
• 负责人: Natalie K Thulin
• 金额: $ 4.46万
• 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/10759369
• 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; Endosomes; Erythrocytes; Faculty; Family; Genes; Genetic Predisposition to Disease; Goals; Heme; Hemophagocytic Lymphohistiocytoses; Human; Immunosuppression; In Vitro; Infection; Inflammation; Inflammatory; Innate Immune Response; Institution; Interferon Type I; Interferons; Intermittent Pyrexia; Macrophage; 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; cytokine; cytokine release syndrome; cytopenia; effective therapy; experimental study; familial hemophagocytic lymphohistiocytosis; human disease; in vitro Assay; in vivo; inducible gene expression; insight; member; monocyte; mouse model; novel; overexpression; receptor; sensor; synergism; 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.

项目摘要/摘要 这项研究的目的是研究炎症性巨噬细胞和疾病的发展 巨噬细胞激活综合征（MAS）。 MAS是风湿性的严重且可能致命的并发症 疾病或病毒感染。 MAS的特征是细胞质的发展，包括贫血和 血栓细胞减少症和嗜型胞菌细胞的积累 - 活化的巨噬细胞，吞噬红色 血细胞（RBC）。我将在全身性狼疮的小鼠模型中研究赞助的MAS样疾病 红斑。在TLR7.1模型中，通过 内体单链RNA传感器收费受体7（TLR7）驱动慢性注射，随后进行 MAS病。 TLR7.1小鼠患有血小板减少症，贫血和新型嗜血细胞种群， 炎症性嗜血细胞（IHPC），它与Ly6CHI单核细胞有所区别。此外，在此 模型，贫血的发展与RBC的IHPC吞噬作用呈正相关，表明IHPC 活动可能是驱动疾病。 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开发相关。 IRF5信号传导对于炎症巨噬细胞的发展至关重要 在这种情况下，几种炎症性疾病。我们实验室的先前工作表明，IRF5消融体内 改善急性TLR7信号传导下游的IHPC分化。但是，在体内TLR7-的背景下 驱动的MAS，IRF5信号在IHPC产生和MAS疾病中的作用尚不清楚。在初步数据中，我 在TLR7.1小鼠中显示通过IRF5信号对于IHPC发育，IHPC RBC吞噬作用和 贫血和血小板减少症指示MAS疾病的发展。基于这些发现，我的目标 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中的作用 分化和MAS疾病（AIM 1），并确定其他信号与TLR7协同驱动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，完成 在拟议的研究以及此处描述的其他培训中，我可以追求自己的目标 成为独立的调查员和教职员工，专注于教育。