A novel mechanism of rheumatoid arthritis-associated pain

类风湿性关节炎相关疼痛的新机制

• 批准号: 9365968
• 负责人: Lintao Qu
• 金额: $ 35.97万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-06 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9365968
• 关键词: 3' Untranslated Regions; Acute; Address; Affect; Afferent Neurons; Ankle; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen-Antibody Complex; Antigens; Arthralgia; Arthritis; Autoimmune Diseases; Behavior; Bioinformatics; Biological; Biological Assay; Biological Response Modifier Therapy; Calcium; Cartilage; Cells; Chronic; Complex; Data; Development; Disease; Down-Regulation; Electrophysiology (science); Genetic; Goals; Health; Human; Hyperactive behavior; Hyperalgesia; Image; Immune; Immunoglobulin G; Immunohistochemistry; In Situ Hybridization; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Joints; Knock-out; Knockout Mice; Light; Measures; Mediating; Mediator of activation protein; Medical; MicroRNAs; Modeling; Molecular Profiling; Mus; Neurons; Neuropathy; Nociception; Outcome; Pain; Pathogenesis; Patients; Peripheral; Pharmacology; Physiological; Process; Publishing; Reporting; Resistance; Rheumatoid Arthritis; Role; Sensory; Series; Serum; Signal Transduction; Spinal Ganglia; Testing; Therapeutic; Work; arthritic pain; base; crosslink; cytokine; defined contribution; design; experience; in vitro Assay; in vivo; inflammatory pain; joint injury; mRNA Expression; molecular marker; mouse model; novel; overexpression; potential biomarker; protein expression; receptor; therapeutic candidate; therapeutic target

Abstract: Joint pain in rheumatoid arthritis (RA) represents a significant health burden. Although RA pain is often thought to result from inflammation, it often persists even after optimal control of inflammation with currently available therapies, indicating the involvement of other non-inflammatory mechanisms. Yet, such mechanisms are largely unknown. The formation of immunoglobulin G immune complex (IgG-IC) in the serum and affected joints is a key feature of RA. Despite extensive biological studies on the role of IgG-IC and its receptors (Fc gamma receptors, FcγRs) in RA pathogenesis, however, little is known about their contributions to RA pain. Ours and others' studies have revealed that, FcγR type I (FcγRI) is expressed not only in immune cells, but also in a subpopulation of primary sensory neurons. Moreover, FcγRI crosslinking by IgG-IC directly induces neuronal activation in vitro. We have now generated preliminary data that peripheral IgG-IC/FcγRI signaling also mediates in vivo hyperactivity of joint sensory neurons and joint pain, but not joint inflammation, in both naïve and arthritic states. The goal of this proposal is therefore to test the hypothesis that IgG-IC drives a noninflammatory component of RA-associated joint pain through direct activation of neuronal FcγRI. In Aim1, we will define which subtypes of joint-innervating sensory neurons express FcγRI. We will also perform in vivo electrophysiological recordings and calcium imaging on DRG neurons in the intact mouse to determine whether IgG-IC excites and or sensitizes specific subtypes of joint sensory afferents and whether genetic knockout of FcγRI diminishes such effects. We will also test whether IgG-IC is able to evoke acute joint pain through activation of FcγRI under naïve conditions. In addition, we will generate a conditional FcγRI knockout mouse line to specifically and unambiguously address the contributions of neuronal FcγRI in this process. In Aim 2, we will test whether FcγRI expression and function are upregulated in DRG in the setting of a murine model of antigen-induced arthritis (AIA). Using global and conditional FcγRI knockout mice, we will also determine whether FcγRI signaling, particularly in neurons, contributes in vivo to neuronal hyperexcitability and chronic joint pain in AIA and whether such any roles are dissociable from effects on inflammation. In Aim 3, we will identify candidate miRNAs that target FcγRI and ask whether they regulate baseline noccieptive responsiveness to IgG-IC, whether they are downregulated in the setting of AIA, and conversely, whether overexpression of these miRNAs can reduce neuronal hyperexcitability and nociceptive behaviors by suppressing FcγRI expression in the AIA model. These studies promise to illuminate a novel mechanism underlying RA-associated pain. If successful, they will significantly impact the field by defining a strong candidate therapeutic target for pain in RA and other autoimmune disorders involving FcγRI that cannot be adequately controlled by anti-inflammatory treatments.

抽象的： 类风湿关节炎（RA）的关节疼痛代表着重要的健康伯恩。虽然经常想到RA疼痛 由于炎症而导致的，即使在最佳控制炎症之后，它通常仍然存在 疗法，表明其他非炎症机制的参与。但是，这种机制是 在很大程度上未知。在血清中形成免疫球蛋白G免疫复合物（IgG-IC）并影响 关节是RA的关键特征。尽管关于IgG-IC及其接收器的作用的广泛生物学研究（FC 但是，在RA发病机理中，伽马受体，FcγRS），对它们对RA疼痛的贡献知之甚少。 我们的研究表明，FcγRI型（FcγRI）不仅在免疫细胞中表达，而且表达 在原代感觉神经元的亚群中也是如此。此外，IgG-IC通过IgG-IC交联的FcγRI直接诱导 体外神经元激活。现在，我们生成了外围IgG-IC/FcγRI信号传导的初步数据 同时介导关节感觉神经元和关节疼痛的体内过度活跃性，但没有关节感染 天真和艺术状态。因此，该提案的目的是检验IgG-IC驱动A的假设 通过直接激活神经元FcγRI，RA相关关节疼痛的非炎性成分。在AIM1中， 我们将定义哪些联合感官神经元的亚型表达FcγRI。我们还将在体内表演 完整小鼠中DRG神经元上的电生理记录和钙成像，以确定 IgG-IC是否激发了关节感官传统的特定亚型以及遗传的特定亚型 FcγRI的敲除减少了这种影响。我们还将测试IgG-IC是否能够引起急性关节痛 通过在条件下激活FcγRI。此外，我们将产生条件的FcγRI敲除 小鼠系在此过程中专门和明确地解决了神经元FcγRI的贡献。在 AIM 2，我们将测试在鼠的情况下，在DRG中是否在DRG中更新FcγRI的表达和功能 使用全球和条件FcγRI敲除小鼠，我们也将 确定FcγRI信号传导，尤其是在神经元中，在体内是否有助于神经元过度兴奋性和 AIA的慢性关节疼痛以及此类作用是否与对注射的影响分离。在AIM 3中，我们 将识别针对FcγRI的候选miRNA，并询问它们是否调节基线Nocictive 对IgG-IC的响应能力，无论它们是否在AIA的环境中被下调，相反，是否 这些miRNA的过表达可以减少神经元过度兴奋性和伤害性行为 抑制AIA模型中的FcγRI表达。这些研究有望阐明一种新型机制 基本的RA相关疼痛。如果成功，它们将通过定义强大的 RA和其他涉及FcγRI的RA和其他自身免疫性疾病的候选治疗靶点 通过抗炎治疗充分控制。