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: 8824440
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824440
• 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; Inflammatory Arthritis; Interleukin-1; Interleukins; Mediating; Modeling; Molecular; Mus; Pathogenesis; Pathology; Patients; Play; Positioning Attribute; Premature Mortality; Production; Protein Family; Proteins; Regulation; Research; Role; Sampling; Serine Protease; Serum; Severities; Signal Pathway; Signal Transduction; Symptoms; Synovial Fluid; Synovitis; 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-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 Mɸ 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 MΦand 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 ß-dependent inflammatory arthritis mouse models and Mɸ 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 β在多种形式的炎性关节炎（包括痛风性关节炎、系统性发作的幼年特发性关节炎和成人发作的斯蒂尔病）的炎症中起重要作用，并介导滑膜炎症、软骨破坏和过早死亡。在IL-1 β信号转导缺陷小鼠和给予抗IL-1 β生物制剂的患者中进行的研究强烈强调了IL-1 β在这些疾病中发挥的核心作用。IL-1 β主要由巨噬细胞（MΦ）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PYRIN（PYD）和Caspase募集结构域（CARD）组成的基本炎性体衔接子，这是其作为炎性体衔接子的功能所必需的。然而，调节过度释放的机制 IL-1 β在炎症性关节炎中的作用尚不清楚，但在开发未来的治疗方法方面具有巨大的潜力。我们发现了一个家族的小内源性炎性体抑制剂组成的只有一个PYD，我们称之为PYD-only蛋白（POP）。体外研究表明，POP 1与ASC的PYD相互作用，从而破坏炎性小体形成和IL-1 β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了POP 1在维持稳态所需的平衡炎性体反应和预防慢性炎症（如炎性关节炎）中的核心作用。然而，持久性有机污染物还没有在体内进行研究，因为持久性有机污染物是缺乏从小鼠和进化在人类作为中央免疫调节蛋白。我们产生了在M Φ和树突状细胞（DC）中特异性表达POP 1的独特转基因（TG）小鼠，因此现在能够进行这些缺乏的体内研究，并且我们现在进一步提供了迫切需要的第一个条件性炎性小体小鼠模型来研究MΦ和DC的炎症和自身免疫疾病贡献。本申请的目的是使用实验性IL-1 β依赖性炎性关节炎小鼠模型和来自人类关节炎患者的MMP 1来研究POP 1阻断炎性关节炎作为负反馈机制的一部分的机制。我们这项研究的基本原理是，了解POP 1介导的炎症性关节炎的调节，可能会允许开发新的治疗方法来改善炎症性关节炎。此外，我们的研究将通过提供POP家族成员的第一个体内数据和第一个条件性炎性小体分析，为关节炎和其他炎性疾病的调节提供新的见解。