SLAMF7 Regulates Synovial Macrophages in Rheumatoid Arthritis

摘要 类风湿性关节炎的主要病理因素是炎症， 患者，但目前还没有专门针对巨噬细胞的治疗方法。在这一提议中， 我们试图通过了解关节炎中巨噬细胞失调的标志性途径， 调节巨噬细胞活化状态的免疫调节受体。在我们的初步数据中， 分析了来自关节炎患者大队列的滑膜巨噬细胞的RNA测序， 可能调节关节炎中巨噬细胞的基因。在该数据集中，巨噬细胞中的SLAMF 7表达 与疾病活动和炎症高度相关。这种受体由白细胞表达， 通过与其他细胞上的SLAMF 7的同型相互作用来控制它们的激活。细胞质 免疫受体酪氨酸开关基序（ITSM）可以通过这种方式驱动细胞活化或抑制 受体，这取决于细胞类型及其激活状态。然而，这种受体在巨噬细胞上的作用 并没有得到很好的理解。基于初步数据表明，激活这一通路会驱动 炎症细胞因子分泌，我们假设SLAMF 7驱动巨噬细胞活化， 关节炎患者关节内的炎症。这项研究计划的重点是了解 SLAMF 7调节巨噬细胞的活化状态，并确定其对炎性关节炎的贡献。 我们将使用人类细胞（Aim 1）和小鼠模型研究这种受体在巨噬细胞上的作用。 关节炎（目标2）。我们将使用体外测定来确定SLAMF 7如何调节 通过定量细胞因子产生、表面活化和/或细胞毒性的变化， 标记表达和转录组学变化。我们将进一步评估该基因在体内的功能， 使用SLAMF 7缺陷的小鼠，在生殖系中，特别是在巨噬细胞中， 炎症性关节炎。我们希望这些研究将为SLAMF 7如何调节细胞内的蛋白质提供关键的见解。 滑膜巨噬细胞的激活状态，这可能导致针对该途径的新的治疗策略。 除了关于SLAMF 7如何调节关节炎中巨噬细胞功能的突破性发现外， 该项目将为候选人提供计算分析和关节炎小鼠模型的关键技能， 这将使他成为一名成功的医生科学家，领导研究，以了解 关节炎中巨噬细胞功能障碍的途径。

Abstract Macrophages are central to the pathology in rheumatoid arthritis, driving inflammation in joints of affected patients, but there are currently no therapies available that specifically target macrophages. In this proposal, we seek to characterize hallmark pathways of macrophage dysregulation in arthritis by understanding immunomodulatory receptors that regulate macrophage activation states. In our preliminary data, we have analyzed RNA sequencing on synovial macrophages from a large cohort of patients with arthritis to identify genes that may regulate macrophages in arthritis. Within this dataset, SLAMF7 expression in macrophages was highly associated with disease activity and inflammation. This receptor is expressed by leukocytes and controls their activation through homotypic interactions with SLAMF7 on other cells. A cytoplasmic immunoreceptor tyrosine switch motif (ITSM) can drive either activation or inhibition of cells through this receptor, depending on the cell type and its activation state. However, the role of this receptor on macrophages is not well understood. Based on preliminary data suggesting that activation of this pathway drives inflammatory cytokine secretion, we hypothesize that SLAMF7 drives macrophage activation, amplifying inflammation within the joints of patients with arthritis. This research proposal is focused on understanding how SLAMF7 regulates the activation state of macrophages and to define its contribution to inflammatory arthritis. We will study the role of this receptor on macrophages using human cells (Aim 1) and mouse models of arthritis (Aim 2). We will use in vitro assays to determine how SLAMF7 regulates the activation of macrophages from blood and synovial tissue by quantifying changes in cytokine production, surface activation marker expression, and transcriptomic changes. We will further evaluate the function of this gene in vivo by using mice that are deficient for SLAMF7, in the germline and specifically in macrophages, in models of inflammatory arthritis. We expect that these studies will provide key insights into how SLAMF7 regulates the activation state of synovial macrophages, which may lead to new therapeutic strategies targeting this pathway. In addition to groundbreaking discoveries about how SLAMF7 regulates macrophage function in arthritis, this project will provide the candidate with key skills in computational analyses and mouse models of arthritis that will allow him to progress to become a successful physician scientist leading research to understand the pathways of macrophage dysfunction in arthritis.