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（由应用提供）：IL-1ß在各种形式的炎症性关节炎中在炎症中起着重要作用，包括盖蒂关节炎，系统发作的少年特发性关节炎和成人发病的静止病，并介导了综合性感染，软骨销毁，软骨破坏和早期死亡率。 IL-1ß在这些疾病中发挥的核心作用是通过在IL-1ß信号传导不足的小鼠和给药的抗IL-1ß生物制剂的患者中强烈强调的。 IL-1ß主要由巨噬细胞中的炎性症（Mφ）和关节炎产生，也是由中性粒细胞和肥大细胞中的丝氨酸蛋白产生的。 ASC是由pyrin（PYD）和caspase募集域（CARD）组成的必需炎性体适配器，这对于其作为炎性体适配器的功能至关重要。但是，调节IL-1ß在炎性关节炎中的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的潜力。我们发现了一个仅由PYD组成的小型内源性炎性体抑制剂，我们称之为仅PYD蛋白质（POPS）。体外研究表明，POP1与ASC的PYD相互作用，从而破坏了IL-1ß炎症体形成和释放所必需的必需PYD PYD相互作用。我们的初步体内研究进一步支持POP1在维持体内稳态和预防慢性炎症（例如炎症性关节炎）中所必需的平衡炎性反应中的核心作用。然而，尚未在体内研究流行音乐，因为小鼠缺乏流行音乐，并在人类中演变为中央免疫调节蛋白。我们产生了在Mφ和树突细胞（DC）中表达POP1的独特转基因（TG）小鼠，因此现在可以进行这些缺乏体内研究的缺乏，现在我们进一步提供了急需的急需的有条件炎症小鼠模型，以研究炎症性和自身免疫性疾病的贡献，并贡献了Mφ和DC的贡献。该应用的目的是研究POP1通过实验性反馈机制阻止炎症性关节炎的机制 人类关节炎患者的IL-1ß依赖性炎症性关节炎小鼠模型和Mφ。我们对这项研究的理由是，了解POP1介导的炎症性关节炎调节，可能可以开发出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流行家庭成员提供第一个体内数据和第一个有条件的炎性体分析，从而为关节炎和其他炎症性疾病的调节提供新的见解。