Identifying a novel link between two potent proangiogenic cascades in RA

鉴定 RA 中两个有效的促血管生成级联反应之间的新联系

• 批准号: 8639074
• 负责人: SHIVA SHAHRARA
• 金额: $ 7.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639074
• 关键词: Adult; Angiogenesis Inhibition; Angiogenic Factor; Arthritis; Autoimmune Diseases; Binding; Blood Cells; Blood Vessels; CCL19 gene; CCL21 gene; Cell physiology; Cells; Chemotactic Factors; Chronic; Data; Disease; Disease Progression; Endothelial Cells; Event; Experimental Arthritis; Fibroblasts; Fostering; Genes; Homing; Hypoxia; Infiltration; Inflammatory; Interleukin-17; Joints; Lead; Leukocytes; Ligands; Ligation; Link; Mediating; Microarray Analysis; Myeloid Cells; Osteitis; Pathogenesis; Pathology; Patients; Play; Process; Production; Rheumatoid Arthritis; Role; Signal Transduction; Stem cells; Synovial Fluid; Synovial Membrane; T-Lymphocyte; Testing; Therapeutic; Tissues; Tube; Validation; Vascular Endothelial Growth Factors; Vascularization; Wild Type Mouse; angiogenesis; base; insight; interest; joint destruction; macrophage; migration; mouse model; neovascularization; new therapeutic target; novel; novel therapeutic intervention; public health relevance; sensor; translational study

DESCRIPTION (provided by applicant): RA is a chronic inflammatory autoimmune disorder that starts in the young to middle adult years and may lead to complete joint destruction. There is no cure for RA at present and a substantial percentage of patients do no respond to current therapy, therefore novel therapeutic approaches are urgently needed. Angiogenesis is an early and a critical event that fosters RA chronic inflammation and bone erosion by facilitating unbalanced leukocyte migration and pannus formation. Hence inhibition of angiogenesis may lead to identifying novel therapeutic approaches for RA. Macrophages are hypoxia sensors that initiate and maintain angiogenesis in RA synovium. We found that CCR7 was the most highly upregulated gene in macrophages obtained from RA synovial fluid compared to the normal myeloid cells. Consistently macrophages in the RA synovial tissue lining and endothelial cells in the sublining express elevated levels of CCR7 and its ligand CCL21. We uncovered that synovial CCL21 but not CCL19 is a novel and potent chemoattractant for CCR7+ endothelial cells, which plays a pivotal role in RA tube and blood vessel formation. In RA synovial tissue explants, CCL21 driven angiogenesis can be also induced indirectly through VEGF production. We found that the endothelial CCL21 and CCR7 expression is modulated by IL-17 cascade. We further document that that CCL21 is the missing link between IL-17 and VEGF mediated vascularization as CCL21 blockade markedly suppresses IL-17 induced VEGF expression. Based on our supportive data, we hypothesize that angiogenesis is directly promoted by CCL21 ligation to endothelial CCR7 and indirectly induced through VEGF production from RA synovial tissue fibroblasts. We also postulate that CCL21 links the IL-17 and VEGF angiogenesis process, therefore blockade of CCL21/CCR7 cascade will disrupt the IL-17 and VEGF interconnection, thus resolving RA neovascularization. Hence novel translational studies are proposed to provide an in depth understanding of how CCL21/CCR7 cascade is connected to IL-17 mediated arthritis and vascularization. Moreover we will examine the underlying mechanism by which ligation of CCL21 to CCR7 contributes to RA angiogenesis and whether disruption of CCL21 binding to CCR7 can be used as a promising new therapeutic target in RA through disconnecting the link between IL-17 and VEGF mediated neovascularization.

描述（由申请人提供）：RA 是一种慢性炎症性自身免疫性疾病，始于青年至中年，可能导致关节完全破坏。目前，RA 尚无治愈方法，并且相当一部分患者对当前的治疗没有反应，因此迫切需要新的治疗方法。 血管生成是一个早期且关键的事件，它通过促进不平衡的白细胞迁移和血管翳形成而促进 RA 慢性炎症和骨侵蚀。因此，抑制血管生成可能会导致确定 RA 的新治疗方法。巨噬细胞是缺氧传感器，可启动和维持 RA 滑膜中的血管生成。我们发现，与正常骨髓细胞相比，从 RA 滑液中获得的巨噬细胞中，CCR7 是上调程度最高的基因。 RA滑膜组织内层中的巨噬细胞和亚层中的内皮细胞一致表达升高水平的CCR7及其配体CCL21。我们发现滑膜 CCL21 而不是 CCL19 是 CCR7+ 内皮细胞的新型有效趋化剂，在 RA 管和血管形成中发挥着关键作用。在 RA 滑膜组织外植体中，CCL21 驱动的血管生成也可以通过 VEGF 的产生间接诱导。我们发现内皮细胞 CCL21 和 CCR7 的表达受到 IL-17 级联的调节。我们进一步证明，CCL21 是 IL-17 和 VEGF 介导的血管化之间缺失的环节，因为 CCL21 阻断显着抑制 IL-17 诱导的 VEGF 表达。 基于我们的支持性数据，我们假设血管生成是通过 CCL21 与内皮 CCR7 连接直接促进的，并通过 RA 滑膜组织成纤维细胞产生 VEGF 间接诱导的。我们还假设CCL21连接IL-17和VEGF血管生成过程，因此阻断CCL21/CCR7级联将破坏IL-17和VEGF的互连，从而解决RA新生血管形成。因此，提出了新的转化研究，以深入了解 CCL21/CCR7 级联如何与 IL-17 介导的关节炎和血管化相关。此外，我们将研究 CCL21 与 CCR7 连接促进 RA 血管生成的潜在机制，以及通过断开 IL-17 和 VEGF 介导的新血管形成之间的联系，破坏 CCL21 与 CCR7 的结合是否可以用作 RA 有希望的新治疗靶点。