Reversal of Inflammatory Processes in CGD

描述（由申请人提供）：慢性肉芽肿病（CGD）是一种由吞噬细胞NADPH氧化酶突变引起的遗传性疾病。虽然功能氧化酶的丧失导致免疫缺陷，但显著的疾病发病率与过度的且通常无菌的炎症（例如阻塞性肉芽肿、结肠炎和自身免疫）相关。NADPH氧化酶下游的信号提供了必要的炎症控制，但知之甚少。数据支持通过吞噬CGD嗜中性粒细胞的信号传导以及它们被CGD巨噬细胞识别和吞噬（胞吞作用）是有缺陷的;这些过程通常导致抗炎信号（例如TGF β）的产生，并且是解决炎症所需的。具体而言，假设NADPH氧化酶中活性氧物质的缺失导致：i）活化和垂死的CGD中性粒细胞上促进巨噬细胞识别和清除所需的信号显示不足，和ii）巨噬细胞PPARγ（炎症和巨噬细胞编程为巨噬细胞增多症的主控制器）不足。炎症编程在CGD中持续存在，巨噬细胞无法清除垂死的中性粒细胞，这反过来又会积聚、恶化和加剧炎症和自身免疫。本研究的具体目的是：i）确定氧化剂和过氧化物酶体增殖物激活受体的正常作用;γ在巨噬细胞编程中的作用及其与CGD中潜在的细胞增殖缺陷和炎症介质过度产生的关系，ii）定义了PPARγ激动剂在CGD巨噬细胞功能恢复中的作用，iii）定义了在PPARγ激动过程中由替代机制产生的氧化剂在逆转CGD中性粒细胞和巨噬细胞功能障碍中的作用。本研究将使用复杂的生化、遗传和药理学方法在鼠和人CGD中性粒细胞和单核细胞/巨噬细胞中进行。将采用明确定义的鼠CGD肉芽肿性炎症模型，并与人CGD吞噬细胞中的探索性终点一起，i）阐明ROS产生缺陷与吞噬细胞功能紊乱之间的相互关系，ii）确定恢复的PPARγ信号传导是否以及如何逆转受损的细胞增殖和炎症反应。一个新的假说来解释持续性炎症反应在CGD沿着其缓解通过过氧化物酶体增殖物激活受体γ将支持一种新的治疗方法。本研究旨在作为一项现有治疗（可用于治疗CGD患者的PPARγ激动剂）的临床前试验。需要彻底了解CGD和正常情况下巨噬细胞编程和PPARγ信号在识别和清除凋亡细胞中的作用。这些发现也应该给予关键的洞察其他炎症性疾病状态，其中巨噬细胞编程和识别凋亡细胞似乎是有缺陷的。

DESCRIPTION (provided by applicant): Chronic Granulomatous Disease (CGD) is a genetic disease resulting from mutation of the phagocyte NADPH oxidase. While loss of the functioning oxidase results in immunodeficiency, significant disease morbidity is associated with exaggerated, and often sterile, inflammation (e.g. obstructing granuloma, colitis and autoimmunity). Signals downstream of the NADPH oxidase provide necessary control of inflammation, but are poorly understood. Data support that signaling by apoptosing CGD neutrophils and their recognition and engulfment (efferocytosis) by CGD macrophages are defective; these processes ordinarily result in production of anti-inflammatory signals (e.g. TGFß), and are required to resolve inflammation. Specifically, it is hypothesized that absence of reactive oxygen species from the NADPH oxidase results in: i) deficient display of signals on activated and dying CGD neutrophils needed to facilitate macrophage recognition and clearance, and ii) deficient macrophage PPARγ , a master controller of inflammation and macrophage programming for efferocytosis. Inflammatory programming persists in CGD with macrophages unable to clear dying neutrophils, which in turn, accumulate, deteriorate, and fuel exaggerated inflammation and autoimmunity. The specific aims of this investigation are to i) define the normal role of oxidants and PPAR?\γ in macrophage programming and their relationship to underlying deficient efferocytosis and over-production of inflammatory mediators in CGD, ii) define the actions of PPARγ agonists in the restoration of CGD macrophage functioning and iii) define the role of oxidants produced by alternative mechanism(s) during PPARγ agonism in reversing the dysfunction of CGD neutrophils and macrophages. This investigation will be carried out in murine and human CGD neutrophils and monocyte/macrophages using sophisticated biochemical, genetic and pharmacological approaches. A well-defined model of granulomatous inflammation in murine CGD will be employed, and together with exploratory endpoints in human CGD phagocytes, will i) elucidate the interconnection between defective ROS production and miscued phagocyte function, and ii) determine whether, and how, restored PPARγ signaling reverses impaired efferocytosis and inflammatory responses. A new hypothesis to explain the persistent inflammatory response in CGD along with its mitigation through PPARγ will support a novel therapeutic approach. This investigation is intended to be a pre-clinical trial of an existing therapy, PPARγ agonists, available for treatment of CGD patients. A thorough understanding of macrophage programming and PPARγ signaling in the recognition and clearance of apoptotic cells in CGD and under normal circumstances is needed. Such findings should also give critical insight into other inflammatory disease states in which macrophage programming and recognition of apoptotic cells appears to be defective.