SLAMF7 Regulates Synovial Macrophages in Rheumatoid Arthritis

摘要 巨噬细胞在类风湿性关节炎的病理过程中起中心作用，促使患者关节发炎。 但目前还没有专门针对巨噬细胞的治疗方法。在这份提案中， 我们试图通过了解在关节炎中巨噬细胞调节失调的标志性途径 调节巨噬细胞激活状态的免疫调节受体。在我们的初步数据中，我们有 分析了一大批关节炎患者滑膜巨噬细胞的RNA序列，以确定 可能调节关节炎中巨噬细胞的基因。在这个数据集中，SLAMF7在巨噬细胞中的表达 与疾病活动和炎症高度相关。这种受体由白细胞表达，并且 通过与其他细胞上的SLAMF7同型相互作用来控制它们的激活。一种细胞质 免疫受体酪氨酸开关基序(ITSM)可以通过这种方式驱动细胞的激活或抑制。 受体，取决于细胞类型及其激活状态。然而，该受体在巨噬细胞上的作用 还没有被很好地理解。根据初步数据表明，激活这一途径将推动 炎性细胞因子的分泌，我们假设SLAMF7驱动巨噬细胞激活，放大 关节炎患者关节内的炎症。这项研究计划的重点是了解 SLAMF7调节巨噬细胞的激活状态，并确定其在炎症性关节炎中的作用。 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)。我们将使用体外实验来确定SLAMF7是如何调节 血液和滑膜组织中巨噬细胞通过量化细胞因子产生、表面活化的变化 标记的表达，以及转录的变化。我们将进一步评估该基因在体内的功能 利用SLAMF7缺乏的小鼠，在生殖系中，特别是在巨噬细胞中，在 炎症性关节炎。我们预计，这些研究将为SLAMF7如何监管 滑膜巨噬细胞的激活状态，这可能导致针对这一途径的新的治疗策略。 除了关于SLAMF7如何在关节炎中调节巨噬细胞功能的开创性发现之外，这一发现 该项目将为应聘者提供计算分析和关节炎小鼠模型方面的关键技能 将使他成长为一名成功的内科科学家，领导研究了解 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.