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: 8634025
• 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/8634025
• 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; 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.

说明(申请人提供)：IL-1在各种形式的炎症性关节炎中发挥重要作用，包括痛风性关节炎、全身性青少年特发性关节炎和成人斯蒂尔病，并介导滑膜炎症、软骨破坏和过早死亡。在IL-1信号缺陷小鼠和使用抗IL-1生物制品的患者中的研究强烈强调了IL-1在这些疾病中所起的中心作用。IL-1主要由巨噬细胞中的炎性小体产生，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是由吡喃(PYD)和半胱氨酸天冬氨酸氨基转移酶募集结构域(CARD)组成的必需的炎症体适配器，它们是其作为炎症体适配器发挥功能所必需的。然而，炎症性关节炎中IL-1过度释放的调节机制还知之甚少，但在开发未来的治疗方法方面具有巨大的潜力。我们发现了一类仅由一种PYD组成的小的内源性炎性小体抑制剂家族，我们称之为PYD-Only Proteins(POPS)。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-1β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在维持体内平衡所需的炎症体反应和预防慢性炎症(如炎症性关节炎)方面发挥核心作用。然而，POPs还没有在体内进行研究，因为POPs在小鼠中缺乏，在人类中作为中枢免疫调节蛋白进化而来。我们建立了独特的转基因(TG)小鼠，在M？和树突状细胞(DC)中特异性地表达POP1，因此现在能够承担这些缺乏的体内研究，我们进一步提供了目前迫切需要的第一个条件性炎症小鼠模型，以研究M？和DC在炎症和自身免疫性疾病中的作用。本应用的目的是利用实验性的IL-1依赖的炎性关节炎小鼠模型和人类关节炎患者的M？，研究POP1阻断炎性关节炎的机制，作为负反馈机制的一部分。我们这项研究的基本原理是，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，我们的研究将通过为一个POP家族成员提供第一个活体数据和第一个条件性炎症组分析，为关节炎和其他炎症性疾病的调控提供新的见解。