The Role of IL-17 in Monocyte Migration

IL-17 在单核细胞迁移中的作用

• 批准号: 8105176
• 负责人: SHIVA SHAHRARA
• 金额: $ 7.46万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105176
• 关键词: Acute; Adhesions; Affinity; Animal Model; Arthritis; Binding; Blood Vessels; CCL2 gene; CCL20 gene; CCL23 gene; CD4 Positive T Lymphocytes; Cell Adhesion Molecules; Cell surface; Cells; Chemotactic Factors; Chemotaxis; Chimera organism; Data; Disease; Endothelial Cells; Endothelium; Fibroblasts; Glycoproteins; Goals; Greater sac of peritoneum; Homing; Human; ICAM1 gene; Immigration; Immune; Implant; In Vitro; Inflammation; Inflammatory; Integrins; Interleukin-17; Interleukins; Joints; Leukocyte Rolling; Leukocytes; Ligands; Ligation; Liquid substance; MAPK14 gene; MAPK8 gene; Mediating; Mediator of activation protein; Molecular Conformation; Mus; Pathogenesis; Pathway interactions; Porifera; Production; Recruitment Activity; Research; Rest; Rheumatoid Arthritis; Role; SCID Mice; Selectins; Signal Transduction; Signaling Protein; Site; Stimulus; Synovial Fluid; Synovial Membrane; Tissues; ankle joint; base; chemokine; cytokine; in vivo; joint destruction; macrophage; migration; monocyte; novel; peripheral blood; prevent; public health relevance; receptor; response; therapeutic target; trafficking

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.

描述（由申请人提供）： 项目摘要 研究表明，白细胞介素 (IL)-17 在类风湿关节炎 (RA) 动物模型的发病机制中发挥着重要作用。然而，IL-17 促进疾病的机制尚不完全清楚。 TH-17 细胞是一种不同于 TH1 和 TH2 的新 CD4+ T 细胞谱系，其特征是产生 IL-17。我们发现，与正常外周血 (PB) 相比，RA 滑液 (SF) 中的 TH-17 细胞数量有所增加。腺病毒转移 IL-17 诱导体内单核细胞募集至腹膜腔。在没有其他介质的情况下，IL-17 在 RA SF 中检测到的浓度下对单核细胞具有趋化作用。 IL-17 诱导的单核细胞迁移可通过中和 IL-17 受体 (R) 来消除。我们还证明，与假免疫耗竭相比，IL-17 免疫耗竭显着降低了 RA SF 诱导的单核细胞趋化性。还检查了 IL-17 对单核细胞趋化性的间接影响。 IL-17 激活的 RA 滑膜组织 (ST) 成纤维细胞和体外分化的巨噬细胞 (IVD M$s) 产生 MCP-1 和 CCL20，而 CXCL16 仅在 M$s 中诱导。根据我们的初步数据，我们假设 IL-17 可以通过改变单核细胞上的整合素构象，从而增加其与其内皮上同源配体的结合亲和力，直接诱导单核细胞跨内皮迁移至 RA ST。此外，我们假设 IL-17 通过诱导内皮细胞产生 MCP-1 来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至 RA ST 是通过 IL-17 对单核细胞的直接作用还是通过内皮细胞产生的趋化因子和/或整合素介导的 IL-17 的间接作用或者也许两者兼而有之。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) 小鼠的 RA ST 中； b.研究对单核细胞的 IL-17R 阻断是否会阻止它们响应 IL-17 归巢到 SCID 小鼠中植入的 RA ST； 2：a.检查IL-17是否可以诱导内皮细胞产生单核细胞趋化因子； b.研究 IL-17 是否诱导单核细胞和内皮细胞（ICAM1 和 VCAM1）或两者上的粘附分子激活（LFA1、VLA4）和表达（LFA1、VLA4）； c.研究层流中 IL-17 诱导的单核细胞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 介导单核细胞募集至 RA ST 的机制。那些调节 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会导致炎症。在本提案中，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，并且这种效应发生在 RA 关节液中存在的 IL-17 浓度下。成功完成拟议研究将阐明 IL-17 介导 RA 关节组织中单核细胞迁移的机制。那些调节 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。

项目成果

Role of TH-17 cells in rheumatic and other autoimmune diseases.

• DOI: 10.4172/2161-1149.1000104
• 发表时间: 2011-10
• 期刊: Rheumatology
• 影响因子: 5.5
• 作者: M. Volin;S. Shahrara

Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in rheumatoid arthritis and experimental arthritis.

• DOI: 10.4049/jimmunol.1302998
• 发表时间: 2014-10-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kim SJ;Chen Z;Chamberlain ND;Essani AB;Volin MV;Amin MA;Volkov S;Gravallese EM;Arami S;Swedler W;Lane NE;Mehta A;Sweiss N;Shahrara S
• 通讯作者: Shahrara S