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、全身性青少年特发性关节炎和成年性斯蒂尔氏病）的炎症中发挥重要作用，介导滑膜炎症、软骨破坏和过早死亡。在IL-1ß信号缺陷小鼠和服用抗IL-1ß生物制剂的患者中进行的研究强烈强调了IL-1ß在这些疾病中发挥的核心作用。IL-1ß主要由巨噬细胞中的炎性小体产生（MΦ），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）组成的炎性小体必需适配体，这两个结构域对ASC作为炎性小体适配体的功能至关重要。然而，炎症性关节炎中调节IL-1ß过度释放的机制尚不清楚，但在开发未来治疗方法方面具有巨大潜力。我们发现了一个仅由PYD组成的内源性小炎性体抑制剂家族，我们称之为PYD-only蛋白（pop）。体外研究表明，POP1与ASC的PYD相互作用，从而破坏了炎性体形成和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了POP1在维持体内平衡和预防慢性炎症（如炎症性关节炎）所需的炎性小体反应平衡中的核心作用。然而，持久性有机污染物尚未在体内进行研究，因为持久性有机污染物在小鼠体内缺乏，而在人类体内进化为中枢免疫调节蛋白。我们产生了独特的转基因（TG）小鼠，在MΦ和树突状细胞（DC）中特异性表达POP1，因此现在可以进行这些缺乏的体内研究，我们进一步提供了现在迫切需要的第一条件炎性体小鼠模型来研究MΦ和DC对炎症和自身免疫疾病的贡献。本应用的目的是通过实验研究POP1阻断炎性关节炎作为负反馈机制的一部分的机制