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

• 批准号: 10199939
• 负责人: Betsy J Barnes
• 金额: $ 57.14万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 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/10199939
• 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/antagonist; macrophage; monocyte; mouse model; new therapeutic target; novel; overexpression; pediatric lupus; prevent; systemic juvenile idiopathic arthritis; therapeutic target; transcription factor; transcriptome; transcriptome sequencing

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.

项目概要 巨噬细胞激活综合征（MAS）是一种与风湿性疾病相关的急性并发症。 MAS 是 然而，最常见于系统性幼年特发性关节炎 (sJIA) 和小儿狼疮患者 MAS 可以在病毒感染（例如 EBV）后发生。 MAS 涉及激活的积累 骨髓、脾脏和肝脏中的巨噬细胞吞噬红细胞 (RBC) 白细胞。 MAS 与炎症细胞因子增加、血细胞减少（例如贫血）和 血小板减少症和高血清铁蛋白。如果不进行治疗，MAS 可能是致命的，大多数死亡发生在 sJIA 是由 MAS 造成的。因此，了解风湿性和炎症性 MAS 的潜在机制 疾病对于开发新的治疗干预方法非常重要。识别小说 促进 MAS 的途径，我们重点关注小鼠模型中病理性巨噬细胞的鉴定 马航的。由于红细胞、血小板和白细胞的吞噬作用可能是急性炎症的主要贡献者。 由于 MAS 中出现血细胞减少，我们推断特殊的吞噬细胞可能参与疾病的发病机制。 我们发现，通过内体 TLR7 和 TLR9 的慢性信号传导直接诱导新型细胞的分化。 巨噬细胞群称为炎症噬血细胞 (iHPC)，与 Ly6Chi 不同 单核细胞。 TLR7的转基因过度表达不仅引起了iHPC的发展，而且引起了 致命的 MAS 样疾病可以通过 iHPC 消耗来挽救。继发于 sJIA 和病毒感染的 MAS 与编码 IRF5 的基因变异相关，IRF5 是 TLR 下游激活的转录因子 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 iHPC 分化，并且 IRF5 在我们的小鼠 iHPC 中高度激活 TLR7诱导的MAS模型。该应用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。在本提案中，我们将 1) 测试 假设 TLR7 驱动的 MAS 小鼠模型中 iHPC 分化和疾病需要 IRF5，2) 确定 IRF5 参与 iHPC 分化的机制，以及 3) 检验假设 IRF5 在患有 MAS 的 sJIA 患者的 iHPC 和/或单核细胞中被组成型激活。顺利完成 这些研究将确定 IRF5 是否是 sJIA 和其他疾病中 MAS 的可行治疗靶点 自身免疫性疾病。