The Role of IL-17 in Monocyte Migration

描述（由申请人提供）： 研究表明，白细胞介素（IL）-17在类风湿性关节炎（RA）动物模型的发病机制中起重要作用。然而，IL-17促进疾病的机制尚不完全清楚。TH- 17细胞是不同于TH 1和TH 2的CD 4 + T细胞的新谱系，其特征在于产生IL-17。我们发现RA滑液（SF）中TH-17细胞的数量比正常外周血（PB）增加。腺病毒转移的IL-17诱导体内单核细胞募集到腹膜腔中。在不存在其他介质的情况下，IL-17在RA SF中检测到的浓度下对单核细胞具有趋化性。通过中和IL-17受体（R）消除IL-17诱导的单核细胞迁移。我们还表明，IL-17免疫耗竭显着减少单核细胞趋化诱导RA SF相比，假免疫耗竭。还检查了IL-17对单核细胞趋化性的间接作用。RA滑膜组织（ST）成纤维细胞和体外分化的巨噬细胞（IVD M$s）由IL-17激活产生MCP-1和CCL 20，而CXCL 16仅在M$s中被诱导。基于我们的初步数据，我们假设IL-17可以通过改变单核细胞上的整合素构象，从而增加其与内皮上的同源配体的结合亲和力，直接诱导单核细胞跨内皮迁移到RA ST中。此外，我们假设IL-17通过诱导内皮细胞产生MCP-1介导单核细胞募集到滑膜中。该提案的目的是检查IL-17诱导的单核细胞迁移到RA ST中是通过IL-17对单核细胞的直接作用还是通过由内皮细胞产生的趋化因子和/或整合素介导的IL-17的间接作用，或者可能是两者。该提案的具体目标是：1。确定IL-17是否促进单核细胞募集到移植到严重联合免疫缺陷（SCID）小鼠中的RA ST中; B.研究单核细胞上的IL-17 R阻断是否阻止它们响应于IL-17而在SCID小鼠中归巢至移植的RA ST; 2：a.检查IL-17是否可以从内皮细胞诱导单核细胞趋化因子; B.研究IL-17是否诱导单核细胞和内皮细胞（ICAM 1和VCAM 1）或两者上的粘附分子活化（LFA 1，VLA 4）和表达（LFA 1，VLA 4）; c.研究IL-17诱导的单核细胞在层流中的跨内皮迁移是否取决于其对单核细胞、内皮细胞或两者上表达的粘附分子的影响。成功完成拟议的研究将阐明IL-17介导单核细胞募集到RA ST的机制。调节IL-17诱导的单核细胞迁移的因子可能是RA的潜在治疗靶点。 公共卫生相关性： 项目叙述。在类风湿性关节炎（RA）中，一种称为单核细胞的免疫细胞迁移到关节中有助于炎症。在这项提案中，我们展示了新的数据，表明一种称为IL-17的促炎细胞信号蛋白在单核细胞的迁移中很重要，并且这种作用发生在RA关节液中存在的IL-17浓度下。该研究的成功完成将阐明IL-17介导RA关节组织中单核细胞迁移的机制。这些调节IL- 17诱导的单核细胞迁移的因子可能是RA潜在的治疗靶点。

DESCRIPTION (provided by applicant): Project Summary It has been shown that interleukin (IL)-17 is important in the pathogenesis of animal models of Rheumatoid Arthritis (RA). However, the mechanism by which IL-17 promotes disease is incompletely understood. The TH- 17 cell, a new lineage of CD4+ T cells distinct from TH1 and TH2 is characterized by the production of IL-17. We identified increased numbers of TH-17 cells in RA synovial fluid (SF) compared to normal peripheral blood (PB). Adenovirally transferred IL-17 induced in vivo monocyte recruitment into the peritoneal cavity. IL-17, in the absence of other mediators, was chemotactic for monocytes at the concentrations detected in the RA SF. IL-17-induced monocyte migration was abrogated by neutralizing IL-17 receptor (R). We also demonstrated that IL-17 immunodepletion significantly reduced monocyte chemotaxis induced by RA SF compared to sham immunodepletion. The indirect effects of IL-17 on monocyte chemotaxis were also examined. RA synovial tissue (ST) fibroblasts and in vitro differentiated macrophages (IVD M$s) activated by IL-17 produced both MCP-1 and CCL20 while CXCL16 was only induced in M$s. Based on our preliminary data we hypothesize that IL-17 can induce monocyte transendothelial migration into the RA ST directly by altering integrin conformation on monocytes and thereby increasing their binding affinity to their cognate ligands on endothelium. Further, we hypothesize that IL-17 mediates monocyte recruitment into the synovium by inducing MCP-1 production by endothelial cells. The goal of this proposal is to examine whether IL-17-induced monocyte migration into the RA ST is through direct effects of IL-17 on monocytes or through the indirect effects of IL-17 mediated by chemokines and/or integrins produced by endothelial cells or perhaps both. The specific aims of this proposal are 1: a. Determine whether IL-17 promotes monocyte recruitment into RA ST engrafted in the severe combined immune deficiency (SCID) mice; b. Investigating whether IL-17R blockade on monocytes prevents their homing to engrafted RA ST in SCID mice in response to IL-17; 2: a. Examine whether IL-17 can induce monocyte chemoattractant chemokines from the endothelial cells; b. Investigate whether IL-17 induces adhesion molecule activation (LFA1, VLA4) and expression (LFA1, VLA4) on monocytes, and endothelial cells (ICAM1 and VCAM1) or both; c. Investigate whether IL-17-induced monocyte transendothelial migration in laminar flow depends on its effect on adhesion molecules expressed on monocytes, endothelial cells or both. Successful completion of the proposed research will elucidate the mechanism by which IL-17 mediates monocyte recruitment into the RA ST. Those factors that regulate IL-17- induced monocyte migration may be potential therapeutic targets in RA. PUBLIC HEALTH RELEVANCE: Project Narrative. In rheumatoid arthritis (RA), migration of a type of immune cells called monocytes into the joint contributes to inflammation. In this proposal we demonstrate novel data showing that a pro-inflammatory cell signaling protein called IL-17 is important in the migration of monocytes, and that this effect occurs at the concentrations of IL-17 present in RA joint fluid. Successful completion of the proposed research will elucidate the mechanism by which IL-17 mediates monocyte migration in RA joint tissue. Those factors that regulate IL- 17-induced monocyte migration may be potential therapeutic targets in RA.