A Regulatory Checkpoint in the Pathogenesis of Inflammatory Arthritis

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，调节机制的过度释放

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.