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

项目摘要/摘要 本研究的目的是探讨炎性巨噬细胞与疾病的发展。 巨噬细胞激活综合征(MAS)。MAS是风湿性疾病的一种严重且可能致命的并发症。 疾病或病毒感染。多发性硬化症的特点是出现细胞减少症，包括贫血和 血小板减少和吞噬红血球的巨噬细胞聚集 血细胞(RBC)。我将研究系统性红斑狼疮小鼠模型中的自发性MAS样疾病 红斑狼疮。在TLR7.1模型中，过表达和结构性活跃的信号通过 内体单链RNA传感器Toll样受体7(TLR7)驱动慢性炎症和随后的 马斯病。TLR7.1小鼠出现血小板减少、贫血和一种新的噬血细胞群， 炎性噬血细胞(IHPC)，自发分化为Ly6chi单核细胞。此外，在这方面 模型中，贫血的发生与红细胞的IHPC吞噬功能呈正相关，提示IHPC 运动可能是导致疾病的原因。 在人类中，编码转录因子干扰素调节因子5(IRF5)的基因中的SNPs是 与MAS开发相关。IRF5信号对炎性巨噬细胞的发育至关重要 在此背景下，几种炎症性疾病。我们实验室以前的工作表明，在体内进行IRF5消融 改善急性TLR7信号下游的IHPC分化。然而，在体内TLR7的背景下- 在MAS的驱动下，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的信号对于IHPC的发展、IHPC的红细胞吞噬和 贫血和血小板减少预示着MAS疾病的发展。基于这些发现，我的目标是 建议确定IRF5信号在TLR7驱动的IHPC中的作用，特别是在Ly6chi单核细胞中 分化和MAS病(AIM 1)，并确定哪些其他信号与TLR7协同推动IHPC 分化和MAS病，特别关注血红素和I型干扰素(AIM 2)。总体而言，完成 以及我在这里描述的额外培训，将使我能够实现我的目标 成为一名专注于教育的独立调查员和教员。

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.