A Regulatory Checkpoint in the Pathogenesis of Inflammatory Arthritis

炎症性关节炎发病机制的监管检查点

• 批准号: 9246985
• 负责人: Christian Stehlik
• 金额: $ 37.9万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246985
• 关键词: Acute; Adaptor Signaling Protein; Adult-Onset Still' s Disease; Affect; Arthritis; Autoimmune Diseases; Biochemical; Biological; CASP1 gene; Cartilage; Caspase; Cell Wall; Chronic; Chronic Childhood Arthritis; Communicable Diseases; Crystallization; Data; Dendritic Cells; Development; Disease; Experimental Models; Family; Family member; Feedback; Future; Goals; Gouty Arthritis; Health; Healthcare Systems; Homeostasis; Human; Immune; Impairment; In Vitro; Inflammasome; Inflammation; Inflammatory; Inflammatory Arthritis; Interleukin-1 beta; Mediating; Modeling; Molecular; Mus; Pathogenesis; Pathology; Patients; Play; Positioning Attribute; Premature Mortality; Production; Protein Family; Proteins; Recruitment Activity; Regulation; Research; Role; Sampling; Serine Protease; Serum; Severities; Signal Pathway; Signal Transduction; Symptoms; Synovial Fluid; Synovitis; Time; Tissues; Transgenic Mice; Transgenic Organisms; Uric Acid; base; design; genetic regulatory protein; improved; in vivo; inhibitor/antagonist; insight; macrophage; mast cell; mouse model; neutrophil; novel; novel therapeutic intervention; novel therapeutics; prevent; public health relevance; response; therapy design; tool; treatment strategy

DESCRIPTION (provided by applicant): IL-1ß plays a significant role in inflammation in a variety of forms of inflammatory arthritis, including gouty arthritis, Systemic-onset Juvenile idiopathic arthritis and adult-onset Still's disease and mediates synovial inflammation, cartilage destruction, and premature mortality. The central role that IL-1ß plays in these diseases is strongly emphasized by studies in IL-1ß signaling deficient mice and in patients administered anti-IL-1ß biologicals. IL-1ß is primarily produced by inflammasomes in macrophages (MΦ) and in arthritis also by serine proteases in neutrophils and mast cells. ASC is the essential inflammasome adaptor composed of PYRIN (PYD) and Caspase recruitment domains (CARD), which are essential for its function as inflammasome adaptor. However, the mechanism regulating the excessive release of IL-1ß in inflammatory arthritis is poorly understood, but has tremendous potential for developing future therapies. We discovered a family of small endogenous inflammasome inhibitors composed of only a PYD, which we refer to as PYD-only proteins (POPs). In vitro studies show that POP1 interacts with the PYD of ASC and thereby disrupts the essential PYD-PYD interaction necessary for inflammasome formation and release of IL-1ß. Our preliminary in vivo studies further support a central role of POP1 in maintaining a balanced inflammasome response necessary for homeostasis and preventing chronic inflammation, such as in inflammatory arthritis. However, POPs have not been studied in vivo, because POPs are lacking from mice and evolved in humans as central immune regulatory proteins. We generated unique transgenic (TG) mice expressing POP1 specifically in MΦ and dendritic cells (DC) and therefore now in the position to undertake these lacking in vivo studies and we further provide now the urgently needed first conditional inflammasome mouse model to study inflammatory and auto-immune disease contribution of MΦ and DC. The objective of this application is to investigate the mechanism by which POP1 blocks inflammatory arthritis as part of a negative feedback mechanism, using experimental IL-1ß-dependent inflammatory arthritis mouse models and MΦ from human arthritis patients. Our rationale for this research is that understanding the POP1-mediated regulation of inflammatory arthritis, might allow the development of novel therapeutic approaches to ameliorate inflammatory arthritis. In addition, our study will provide novel insights into the regulation of arthritis and other inflammatory diseases by provide the first in vivo data for a POP family member and a first conditional inflammasome analysis.

描述（由申请人提供）：IL-1ß 在多种形式的炎性关节炎（包括痛风性关节炎、全身性幼年特发性关节炎和成人斯蒂尔氏病）的炎症中发挥重要作用，并介导滑膜炎症、软骨破坏和过早死亡。 IL-1ß 信号传导缺陷小鼠和服用抗 IL-1ß 生物制剂的患者的研究强烈强调了 IL-1ß 在这些疾病中发挥的核心作用。 IL-1ß 主要由巨噬细胞 (MΦ) 中的炎症小体产生，在关节炎中，也由中性粒细胞和肥大细胞中的丝氨酸蛋白酶产生。 ASC 是重要的炎症小体接头，由 PYRIN (PYD) 和 Caspase 募集结构域 (CARD) 组成，这对于其作为炎症小体接头的功能至关重要。然而，人们对调节炎症性关节炎中 IL-1ß 过度释放的机制知之甚少，但在开发未来疗法方面具有巨大潜力。我们发现了一个仅由 PYD 组成的小型内源性炎症小体抑制剂家族，我们将其称为仅 PYD 蛋白 (POP)。体外研究表明，POP1 与 ASC 的 PYD 相互作用，从而破坏炎症小体形成和 IL-1ß 释放所必需的 PYD-PYD 相互作用。我们的初步体内研究进一步支持 POP1 在维持体内平衡和预防慢性炎症（例如炎症性关节炎）所必需的平衡炎症反应中发挥核心作用。然而，POPs 尚未在体内进行研究，因为 POPs 在小鼠中缺乏，并且在人类中进化为中央免疫调节蛋白。我们生成了在 MΦ 和树突状细胞 (DC) 中特异性表达 POP1 的独特转基因 (TG) 小鼠，因此现在能够开展这些缺乏的体内研究，并且我们进一步提供现在急需的第一个条件炎症体小鼠模型来研究 MΦ 和 DC 对炎症和自身免疫性疾病的贡献。本应用的目的是通过实验研究 POP1 作为负反馈机制的一部分阻断炎症性关节炎的机制。 IL-1ß 依赖性炎症关节炎小鼠模型和来自人类关节炎患者的 MΦ。我们进行这项研究的理由是，了解 POP1 介导的炎症性关节炎调节可能有助于开发新的治疗方法来改善炎症性关节炎。此外，我们的研究将为 POP 家族成员提供第一个体内数据和第一个条件炎症体分析，从而为关节炎和其他炎症性疾病的调节提供新的见解。