Identifying a novel link between two potent proangiogenic cascades in RA

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，可能导致完全的关节破坏。目前还没有治愈RA的方法，而且相当大比例的患者对目前的治疗没有反应，因此迫切需要新的治疗方法。血管生成是一个早期和关键的事件，通过促进不平衡的白细胞迁移和血管形成，促进RA慢性炎症和骨侵蚀。因此，抑制血管生成可能会导致寻找新的治疗RA的方法。巨噬细胞是启动和维持RA滑膜血管生成的缺氧传感器。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是上调幅度最大的基因。RA滑膜组织内层的巨噬细胞和下层的内皮细胞一致表达CCR7及其配体CCL21水平升高。我们发现滑膜CCL21而不是CCL19是CCR7+内皮细胞的一种新型有效的化学引诱剂，CCR7+内皮细胞在RA管和血管形成中起关键作用。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IL-17级联调节。我们进一步证明CCL21是IL-17和VEGF介导的血管化之间缺失的一环，因为CCL21阻断可显著抑制IL-17诱导的VEGF表达。基于我们的支持性数据，我们假设CCL21连接内皮细胞CCR7直接促进血管生成，并通过RA滑膜组织成纤维细胞产生VEGF间接诱导血管生成。我们还假设CCL21连接了IL-17和VEGF的血管生成过程，因此阻断CCL21/CCR7级联将破坏IL-17和VEGF的互连，从而解决RA的新生血管形成。因此，我们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CCL21与CCR7结合的中断是否可以通过断开IL-17和VEGF介导的新生血管形成之间的联系，作为RA有希望的新治疗靶点。

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.