Investigating the IL-4/13 Axis in Osteoarthritis

研究骨关节炎中的 IL-4/13 轴

• 批准号: 10438519
• 负责人: William H Robinson
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438519
• 关键词: Anti-Inflammatory Agents; Asthma; Award; Basophils; Biological Markers; Blood; Bone remodeling; Caring; Cartilage; Cells; Chondrocytes; Clinical; Clinical Trials; Degenerative polyarthritis; Development; Disease; Drug Targeting; Evaluation; Exhibits; FDA approved; Fatty acid glycerol esters; Fibroblasts; Functional disorder; Gene Expression; Gene Expression Profiling; Genetic; Grant; Health; Hematopoietic; Hemorrhage; Homeostasis; Human; IL-13Ralpha1; IL4 gene; Immunity; In Situ; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-13; Interleukin-4; Intervention; Investigation; Joints; Lead; Liquid substance; Macrophage Activation; Medial meniscus structure; Mediating; Mediator of activation protein; Military Personnel; Molecular; Mus; Myeloid Cells; Osteoblasts; Osteoclasts; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Play; Production; Rehabilitation Outcome; Rehabilitation therapy; Reporter; Research; Role; STAT6 gene; Sampling; Serum; Severities; Signal Transduction; Synovial Fluid; Testing; Th2 Cells; Therapeutic; Tissues; Tranexamic Acid; Translating; Translations; Veterans; base; cell type; cytokine; healing; in vivo; interleukin-13 receptor; joint injury; macrophage; mast cell; military veteran; mouse model; predictive marker; prevent; receptor; reduce symptoms; response; success; targeted agent; therapeutic candidate

Many Veterans and civilians sustain traumatic joint injuries, which frequently lead to joint dysfunction and development of osteoarthritis (OA). Existing treatments for joint injury and OA only alleviate symptoms, and are ineffective in promoting healing or preventing OA. Increasing evidence implicates “low-grade” inflammation following joint injury in development of OA. A better understanding of the underlying inflammatory mechanisms and identification of pharmacologic agents that target these mechanisms could transform care for military personnel, Veterans, and civilians with traumatic joint injuries and/or that are developing OA. Our preliminary studies suggest that Type II immunity and the IL-4/IL-13 inflammatory axis are dysregulated in OA. In this proposal, we aim to elucidate the roles of Type II immunity and the IL-4/IL-13 axis in the development of OA. Type II immunity and the IL-4/IL-13 inflammatory axis have been widely implicated in atopic diseases, such as asthma, but have not been extensively studied in the context of OA. We found that IL-4 is downregulated, while IL-13 levels are elevated, in the synovial fluids of individuals with OA. Our findings showed that genetic deficiency in IL-4 leads to more severe OA in mice after destabilization of the medial meniscus (DMM), while IL-13 may promote OA and thereby play an opposing role. Our in vitro studies showed IL-13 induces pathogenic activation of osteoblasts and fibroblasts; while IL-4 promotes protective M2 macrophage phagocytosis of pro-inflammatory cartilage debris and inhibits activation of osteoclasts. We found that pharmacologic inhibition of mast cells, which are major producers of IL-13, prevented OA in mice. Nevertheless, important questions remain about the mechanisms through which the IL-4/IL-13 axis mediates inflammatory responses following joint injury and in OA. We hypothesize that IL-4 and IL-13 mediate distinct responses in different cell types by signaling through the type-I or type-II cellular receptors, respectively. We hypothesize that following joint injury dysregulated activation of mast cells, basophils, ILC2 cells, and/or Th2 cells results in the production of IL-13. Further, we hypothesize that dysregulated IL-4/IL-13 expression leads to activation of osteoblasts and fibroblasts, loss of osteoclast inhibition, and dysregulated macrophage polarization. Finally, we hypothesize that, together, these changes disrupt homeostasis following joint injury or other insult and lead to development of OA. To test these hypotheses, Aim 1 will characterize the role of Type II immunity in the development of OA through analysis of the IL-4 and IL-13-producing cell types in OA synovial and infrapatellar fat pad tissues, and by analyzing in vivo the contributions of these cell types to OA development. Aim 2 will investigate the molecular mechanisms by which IL-4 and IL-13 regulate protective and pathogenic cellular responses in macrophages, osteoclasts, osteoblasts, synovial fibroblasts, and chondrocytes that contribute to OA. Aim 3 will identify blood biomarkers predictive of OA and the severity of OA. Aim 4 will genetically and pharmacologically target the IL-4/IL-13 pathway to prevent OA following DMM in mice. Importantly, Aim 4 will focus on FDA- approved drugs that target the IL-4/IL-13 axis, thereby providing a path for rapid translation and evaluation of promising candidates for efficacy in preventing OA in humans. If successful, the proposal will elucidate the role of Type II immunity and the IL-4/IL-13 inflammatory axis in the development of OA, and identify candidate therapeutics that can be rapidly translated into clinical trials to evaluate their ability to prevent or treat OA.

许多退伍军人和平民遭受创伤性关节损伤，这经常导致关节功能障碍和 骨关节炎（OA）的发展。现有的关节损伤和骨关节炎治疗方法只能缓解症状，而且 对促进愈合或预防 OA 无效。越来越多的证据表明“低度”炎症 OA 发展过程中的关节损伤后。更好地了解潜在的炎症机制 针对这些机制的药物的鉴定可以改变对军事的护理 患有关节外伤和/或患有骨关节炎的人员、退伍军人和平民。我们的初步 研究表明 OA 中 II 型免疫和 IL-4/IL-13 炎症轴失调。在这个 该提案的目的是阐明 II 型免疫和 IL-4/IL-13 轴在 OA 发展中的作用。 II 型免疫和 IL-4/IL-13 炎症轴广泛涉及特应性疾病，例如 哮喘，但尚未在 OA 背景下进行广泛研究。我们发现 IL-4 下调，而 骨关节炎患者的滑液中 IL-13 水平升高。我们的研究结果表明，遗传 IL-4 缺乏会导致小鼠内侧半月板 (DMM) 不稳定后出现更严重的 OA，而 IL-13 可能会促进 OA，从而起到相反的作用。我们的体外研究表明 IL-13 诱导 成骨细胞和成纤维细胞的致病性激活；而 IL-4 则促进保护性 M2 巨噬细胞 吞噬促炎软骨碎片并抑制破骨细胞的活化。我们发现 对肥大细胞（IL-13 的主要产生者）进行药物抑制可预防小鼠的 OA。 然而，关于 IL-4/IL-13 轴介导的机制仍然存在重要问题。 关节损伤后和 OA 中的炎症反应。我们假设 IL-4 和 IL-13 介导不同的 分别通过 I 型或 II 型细胞受体发出信号来响应不同细胞类型。我们 假设关节损伤后肥大细胞、嗜碱性粒细胞、ILC2 细胞和/或 Th2 细胞的激活失调 细胞会产生 IL-13。此外，我们假设 IL-4/IL-13 表达失调导致 成骨细胞和成纤维细胞的激活、破骨细胞抑制的丧失以及巨噬细胞的失调 极化。最后，我们假设，这些变化共同破坏了关节损伤或关节损伤后的体内平衡。 其他侮辱并导致 OA 的发展。 为了检验这些假设，目标 1 将描述 II 型免疫在 OA 发展中的作用 通过分析 OA 滑膜和髌下脂肪垫组织中产生 IL-4 和 IL-13 的细胞类型，以及 通过体内分析这些细胞类型对 OA 发展的贡献。目标 2 将调查 IL-4 和 IL-13 调节保护性和致病性细胞反应的分子机制 导致 OA 的巨噬细胞、破骨细胞、成骨细胞、滑膜成纤维细胞和软骨细胞。目标3将 确定预测 OA 和 OA 严重程度的血液生物标志物。目标 4 将在遗传和药理学方面 靶向 IL-4/IL-13 通路以预防小鼠 DMM 后的 OA。重要的是，目标 4 将重点关注 FDA—— 已批准的靶向 IL-4/IL-13 轴的药物，从而为快速转化和评估提供了途径 预防人类 OA 的有希望的候选者。如果成功，该提案将阐明其作用 II 型免疫和 IL-4/IL-13 炎症轴在 OA 发展中的作用，并确定候选者 可以快速转化为临床试验的疗法，以评估其预防或治疗 OA 的能力。