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.

项目摘要/摘要 类风湿关节炎（RA）是一种自身免疫性疾病，其标志是炎症和破坏 滑膜关节。即使使用抗TNF等有针对性的疗法，很少有患者可以缓解，并且没有 治愈。 RA患者表现出的残留疾病和复发性耀斑表明，实际解决 滑膜炎症仍然受损。改善了解决炎症和解决机制的知识 急需恢复滑膜稳态。在此提案中，我们研究了一种新颖的促分解机制 RA由滑膜组织内的成纤维细胞驱动。这不同于已知的促分解机制 滑膜和其他地方，由白细胞介导。在RA和其他炎症性疾病中， 除了调节外，基质成纤维细胞已成为局部免疫反应的强大调节剂 组织结构和纤维化。先前确定了成纤维细胞控制的关键机制 RA中的炎症激活，我们现在检查了成纤维细胞是否在 调节炎症分辨率。通过单细胞RNA测序分析，我们观察到了滑膜 在RA缓解过程中，成纤维细胞表达较高水平的AXL受体酪氨酸激酶。 AXL和其他 TAM（TYRO3/AXL/MERTK）家族中的受体具有归因于白细胞的促分解功能。 但是，在滑膜中，我们发现AXL与白细胞相比，成纤维细胞明显高。我们 证明AXL激活后，成纤维细胞下调关键炎症标记和efferocyosose 凋亡细胞，有助于清理。在这里，我们将确定Syovial中的AXL信号传导是否 成纤维细胞代表了一种新型的白细胞独立途径，驱动炎症分辨率。到 在AIM 1中完成此操作，我们定义了AXL对滑膜成纤维细胞炎症极化的影响 识别AXL信号的关键转录和磷酸化靶标。在AIM 2中，我们评估了AXL- 通过滑膜成纤维细胞对凋亡细胞的结合和摄取促进其转录和 针对免疫调节或促进状态的代谢重编程。最后，在AIM 3中，我们测试是否 有针对性的，在滑膜成纤维细胞中AXL的有条件耗竭加剧了关节炎的严重程度或延迟其分辨率 在鼠标模型中。这些研究将共同​​提高我们对成纤维细胞功能和调节的了解 炎症分辨率，有可能为新颖的基质靶向，促进的疗法铺平道路 多种炎症性疾病中的长期缓解。