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: 8480663
• 负责人: Christian Stehlik
• 金额: $ 32.83万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8480663
• 关键词: Acute; Adaptor Signaling Protein; Adult-Onset Still' s Disease; Affect; Arthritis; Biochemical; Biological; Cartilage; Caspase; Caspase-1; Cell Wall; Chronic; Chronic Childhood Arthritis; Communicable Diseases; Data; Dendritic Cells; Development; Disease; Equilibrium; Experimental Models; Family; Family member; Feedback; Future; Goals; Gouty Arthritis; Health; Healthcare Systems; Homeostasis; Human; Immune; Immune System Diseases; In Vitro; Inflammation; Inflammatory; Interleukin-1; Interleukins; Mediating; Modeling; Molecular; Mus; Pathogenesis; Pathology; Patients; Play; Positioning Attribute; Premature Mortality; Production; Protein Family; Proteins; Regulation; Research; Rheumatoid Arthritis; Role; Sampling; Serine Protease; Serum; Severities; Signal Pathway; Signal Transduction; Symptoms; Synovial Fluid; Time; Tissues; Transgenic Mice; Transgenic Organisms; Uric Acid; Work; base; design; genetic regulatory protein; improved; in vivo; inhibitor/antagonist; insight; macrophage; mast cell; mouse model; neutrophil; novel; novel therapeutic intervention; prevent; public health relevance; response; therapy design; tool; treatment strategy

DESCRIPTION (provided by applicant): IL-1¿ 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-1¿ plays in these diseases is strongly emphasized by studies in IL-1 ¿ signaling deficient mice and in patients administered anti-IL-1 ¿ biologicals. IL-1 ¿ is primarily produced by inflammasomes in macrophages (M¿) 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-1 ¿ 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-1 ¿. 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 M¿ 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 M¿ 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-1 ¿ -dependent inflammatory arthritis mouse models and M¿ 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-1¿ IL-1 在多种形式的炎症性关节炎（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-1 研究强烈强调了这些疾病中的作用 ¿信号缺陷小鼠和接受抗 IL-1 治疗的患者 ¿ IL-1 ¿ ASC 主要由巨噬细胞 (M¿) 中的炎症小体产生，关节炎中的关节炎也由中性粒细胞和肥大细胞中的丝氨酸蛋白酶产生。然而，调节 IL-1 过度释放的机制 ¿我们对炎症性关节炎中的作用知之甚少，但在开发未来疗法方面具有巨大潜力。与 ASC 的 PYD 相互作用，从而破坏炎症体形成和 IL-1 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 在小鼠中缺乏并且是进化而来的。我们培育了独特的转基因（TG）小鼠，在 M¿ 中特异性表达 POP1。和树突状细胞（DC），因此现在能够进行这些缺乏的体内研究，我们现在进一步提供急需的第一个条件炎性小鼠模型来研究 M 的炎症和自身免疫性疾病的贡献本申请的目的是使用实验性 IL-1 来研究 POP1 作为负反馈机制的一部分阻断炎症性关节炎的机制。 -依赖性炎症关节炎小鼠模型和M¿我们进行这项研究的理由是，了解 POP1 介导的炎症性关节炎的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，我们的研究将为关节炎和关节炎的调节提供新的见解。通过提供 POP 家族成员的第一个体内数据和第一个条件炎症体分析来研究其他炎症性疾病。