Fibroblast-mediated inflammatory resolution of rheumatoid arthritis

成纤维细胞介导的类风湿性关节炎炎症消退

• 批准号: 10604629
• 负责人: Angela Elizabeth Zou
• 金额: $ 3.99万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604629
• 关键词: Acute; Affect; Apoptotic; Architecture; Arthritis; Autoimmune Diseases; Autoimmunity; Automobile Driving; Binding; Bioinformatics; Biology; Cell Respiration; Cells; Data; Disease; Disease remission; Exhibits; Faculty; Family; Fibroblasts; Fibrosis; Flare; Fostering; Future; Genes; Genetic Transcription; Homeostasis; Immune response; Immunology; Immunosuppression; Impairment; Inflammation; Inflammatory; Inflammatory Arthritis; Joints; K/BxN model; Knock-out; Knockout Mice; Knowledge; Leukocytes; Ligands; MERTK gene; Mediating; Mentors; Metabolic; Microscopy; Modeling; Mus; Nature; Pathologic; Pathway interactions; Patients; Phagocytes; Phosphorylation; Physicians; Play; Population; Principal Investigator; Proteins; Receptor Protein-Tyrosine Kinases; Recurrence; Recurrent disease; Regulation; Research Personnel; Residual Neoplasm; Resolution; Rheumatoid Arthritis; Role; Scientist; Serum; Severities; Signal Transduction; Synovial Cell; Synovial Membrane; Synovial joint; Synovitis; TNF gene; TYRO3 gene; Testing; Tissues; Wild Type Mouse; arthritis therapy; axl receptor tyrosine kinase; doctoral student; experience; healing; immunoregulation; improved; in vivo; inflammatory marker; joint inflammation; metabolic abnormality assessment; mouse model; novel; novel therapeutics; programs; receptor; single-cell RNA sequencing; skills; success; targeted treatment; transcriptome sequencing; transcriptomic profiling; transcriptomics; uptake

Project Summary/Abstract Rheumatoid arthritis (RA) is an autoimmune disease marked by debilitating inflammation and destruction of synovial joints. Even with targeted therapies such as anti-TNF, few patients achieve remission and there is no cure. The residual disease and recurrent flares exhibited by RA patients suggest that bona fide resolution of synovial inflammation remains impaired. Improved knowledge of the mechanisms that resolve inflammation and restore synovial homeostasis is acutely needed. In this proposal, we study a novel pro-resolving mechanism in RA driven by fibroblasts within the synovial tissue. This differs from known pro-resolving mechanisms in synovium and elsewhere, which are mediated by leukocytes. Both in RA and other inflammatory diseases, stromal fibroblasts have emerged as powerful regulators of local immune responses in addition to modulating tissue architecture and fibrosis. Having previously identified key mechanisms by which fibroblasts control inflammatory activation in RA, we now examined whether fibroblasts play similarly instrumental roles in regulating inflammatory resolution. Through single-cell RNA sequencing analyses, we observed that synovial fibroblasts express higher levels of the AXL receptor tyrosine kinase during RA remission. AXL and other receptors in the TAM (TYRO3/AXL/MERTK) family have pro-resolving functions attributed to leukocytes. However, in synovium, we find that AXL is expressed markedly more highly by fibroblasts than leukocytes. We show that upon AXL activation, fibroblasts downregulate key inflammatory markers and also efferocytose apoptotic cells, contributing to their clearance. Here we will determine whether AXL signaling in synovial fibroblasts represents a novel, leukocyte-independent pathway driving inflammatory resolution. To accomplish this, in Aim 1, we define the effects of AXL on synovial fibroblast inflammatory polarization by identifying the key transcriptional and phosphorylated targets of AXL signaling. In Aim 2, we assess how AXL- mediated binding and uptake of apoptotic cells by synovial fibroblasts facilitates their transcriptional and metabolic reprogramming towards immunoregulatory or pro-resolving states. Finally, in Aim 3, we test whether targeted, conditional depletion of AXL in synovial fibroblasts exacerbates arthritis severity or delays its resolution in mouse models. Together, these studies will advance our knowledge of fibroblast function and regulation during inflammatory resolution, potentially paving the way for novel stromal-targeted, pro-resolving therapies that foster long-lasting remission in multiple inflammatory diseases.

项目总结/摘要 风湿性关节炎（RA）是一种自身免疫性疾病，其特征是使人虚弱的炎症和细胞的破坏。 滑膜关节即使使用抗TNF等靶向治疗，也很少有患者达到缓解， 疗方类风湿性关节炎患者表现出的残留疾病和复发性发作表明， 滑膜炎症仍然受损。提高了对解决炎症机制的认识， 恢复滑膜内稳态是迫切需要的。在这个建议中，我们研究了一种新的前解决机制， RA由滑膜组织内的成纤维细胞驱动。这与已知的促分解机制不同， 滑膜和其他地方，其由白细胞介导。在RA和其他炎性疾病中， 基质成纤维细胞除了调节局部免疫应答外， 组织结构和纤维化。先前已经确定了成纤维细胞控制 在RA的炎症激活中，我们现在研究成纤维细胞是否在 调节炎症消退。通过单细胞RNA测序分析，我们观察到， 成纤维细胞在RA缓解期间表达更高水平的AXL受体酪氨酸激酶。AXL和其他 TAM（TYRO 3/AXL/MERTK）家族中的受体具有归因于白细胞的促消退功能。 然而，在滑膜中，我们发现AXL在成纤维细胞中的表达明显高于白细胞。我们 显示在AXL活化后，成纤维细胞下调关键炎症标记物， 凋亡细胞，有助于其清除。在这里，我们将确定是否AXL信号在滑膜 成纤维细胞代表了一种新的、不依赖白细胞的驱动炎症消退的途径。到 为了实现这一点，在目标1中，我们通过以下方式定义了AXL对滑膜成纤维细胞炎症极化的影响： 识别AXL信号传导的关键转录和磷酸化靶点。在目标2中，我们评估AXL- 滑膜成纤维细胞介导的凋亡细胞的结合和摄取促进了它们的转录， 向免疫调节或促消退状态的代谢重编程。最后，在目标3中，我们测试是否 滑膜成纤维细胞中AXL的靶向、条件性消耗加重关节炎的严重程度或延迟其消退 在小鼠模型中。总之，这些研究将推进我们对成纤维细胞功能和调控的认识， 炎症消退，可能为新型基质靶向，促消退疗法铺平道路， 在多种炎症性疾病中的持久缓解。