IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis

系统性幼年特发性关节炎中的 IRF5 和巨噬细胞激活综合征

基本信息

批准号：
10454915
负责人：
Betsy J Barnes
金额：
$ 57.76万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-24 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454915
关键词：
ATAC-seq Acute Adrenal Cortex Hormones Anemia Arthritis Autoimmune Diseases Autoimmunity Blood Platelets Blood specimen Bone Marrow CD14 gene Cells Cessation of life Childhood Chronic Complication Data Development Disease Erythrocytes Ferritin Gene Expression Genes Haplotypes Human Human Herpesvirus 4 In Vitro Inflammatory Interleukin-1 Interleukin-6 Kinetics Leukocytes Liver Macrophage activation syndrome Methods Modeling Molecular NF-kappa B Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Phagocytes Phagocytosis Population Rheumatism Risk Secondary to Serum Signal Transduction Spleen Syndrome Systemic Lupus Erythematosus TLR7 gene Testing Therapeutic Therapeutic Intervention Thrombocytopenia Transgenic Organisms Variant Virus Diseases cell type cytokine cytopenia experimental study genetic variant in vivo inhibitor macrophage monocyte mouse model new therapeutic target novel overexpression pediatric lupus prevent systemic juvenile idiopathic arthritis therapeutic target transcription factor transcriptome transcriptome sequencing

项目摘要

Project Summary Macrophage Activation Syndrome (MAS) is an acute complication associated with rheumatic diseases. MAS is most commonly seen in patients with systemic juvenile idiopathic arthritis (sJIA) and pediatric lupus, however MAS can develop after viral infections, such as with EBV. MAS involves the accumulation of activated macrophages in the bone marrow, spleen and liver that have phagocytosed red blood cells (RBCs) and leukocytes. MAS is associated with increased inflammatory cytokines, cytopenias such as anemia and thrombocytopenia, and high serum ferritin. In the absence of treatment, MAS can be fatal, and most death in sJIA are due to MAS. Thus, understanding the mechanisms underlying MAS in rheumatic and inflammatory diseases is important for the development of new methods of therapeutic intervention. To identify novel pathways contributing to MAS, we focused on the identification of pathologic macrophages in a mouse model of MAS. As the phagocytosis of RBCs, platelets, and leukocytes can be a major contributor to the acute cytopenia seen in MAS, we reasoned that specialized phagocytes may be involved in disease pathogenesis. We found that chronic signaling via endosomal TLR7 and TLR9 directly induced differentiation of a novel macrophage population termed inflammatory hemophagocytes (iHPC), which differentiated from Ly6Chi monocytes. Transgenic overexpression of TLR7 not only caused the development of iHPC, but also caused a lethal MAS-like disease that could be rescued by iHPC depletion. MAS secondary to sJIA and to viral infection is associated with variants in the gene encoding IRF5, a transcription factor activated downstream of TLR signaling in monocytes and macrophages. Our preliminary data show that IRF5 also participates in TLR7- induced iHPC differentiation both in vitro and in vivo, and that IRF5 is hyper-activated in iHPC in our mouse model of TLR7-induced MAS. The premise of this application is that IRF5 signaling downstream of endosomal TLR7 and TLR9 is a critical component of iHPC differentiation and MAS. In this proposal we will 1) Test the hypothesis that IRF5 is required for iHPC differentiation and disease in a mouse model of TLR7-driven MAS, 2) Determine the mechanisms by which IRF5 participates in iHPC differentiation, and 3) Test the hypothesis that IRF5 is constitutively activated in iHPC and/or monocytes from sJIA patients with MAS. Successful completion of these studies will determine whether IRF5 is a viable therapeutic target for MAS in sJIA and other autoimmune diseases.

项目摘要巨噬细胞激活综合征（MAS）是与风湿病有关的急性并发症。 Mas是最常见于全身少年特发性关节炎（SJIA）和小儿狼疮的患者 MAS可以在病毒感染后（例如EBV）发展。 MAS涉及激活的积累骨髓，脾脏和肝脏中的巨噬细胞，具有吞噬红细胞（RBC）和白细胞。 MAS与炎性细胞因子，贫血和诸如贫血和血小板减少症和高血清铁蛋白。在没有治疗的情况下，MAS可能是致命的，并且大多数死亡 SJIA是由于MAS。因此，了解风湿性和炎症中MAS的基础机制疾病对于开发新的治疗干预方法很重要。识别小说有助于MAS的途径，我们专注于小鼠模型中病理巨噬细胞的识别 Mas。 RBC，血小板和白细胞的吞噬作用可能是急性的主要因素在MAS中看到的细胞质减少症，我们认为专门的吞噬细胞可能参与疾病发病机理。我们发现，通过内体TLR7和TLR9通过内体TLR7和TLR9直接诱导了一种新颖的分化巨噬细胞种群称为炎症性胞素细胞（IHPC），与Ly6chi有所不同单核细胞。 TLR7的转基因过表达不仅引起了IHPC的发展，而且还引起了 IHPC耗竭可以营救的致命MAS样疾病。 MAS继发于SJIA和病毒感染与编码IRF5的基因中的变体有关，TLR下游激活了转录因子单核细胞和巨噬细胞中的信号传导。我们的初步数据表明，IRF5也参与TLR7- 在体外和体内诱导的IHPC分化，并且IRF5在鼠标中iHPC过度激活 TLR7诱导的MAS的模型。该应用程序的前提是内体下游的IRF5信号传导 TLR7和TLR9是IHPC分化和MAS的关键组成部分。在此提案中，我们将1）测试在TLR7驱动的MAS的小鼠模型中，IHPC分化和疾病需要IRF5的假设，2）确定IRF5参与IHPC分化的机制，以及3）检验以下假设： IRF5在IHPC和/或MAS患者的单核细胞中进行组成激活。成功完成这些研究将确定IRF5是否是SJIA和其他MAS的可行治疗靶点自身免疫性疾病。