Reversal of Inflammatory Processes in CGD

描述(申请人提供)：慢性肉芽肿性疾病(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会导致免疫缺陷，但严重的疾病发病率与夸大的、通常是无菌的炎症(例如阻塞性肉芽肿、结肠炎和自身免疫)有关。NADPH氧化酶下游的信号提供了必要的炎症控制，但人们对此知之甚少。数据支持，CGD中性粒细胞及其识别和吞噬(泡泡吞噬)信号是有缺陷的；这些过程通常会导致抗炎信号的产生(如转化生长因子？)，并且是消炎所必需的。具体地说，假设NADPH氧化酶上没有活性氧物种导致：i)激活和死亡的cgd中性粒细胞上信号显示不足，促进巨噬细胞识别和清除所需的信号；ii)缺乏巨噬细胞PPARγ，它是炎症和巨噬细胞编程的主控制器，用于吞噬细胞。炎症程序在CGD中持续存在，巨噬细胞无法清除死亡的中性粒细胞，而中性粒细胞反过来积累、恶化，并助长夸大的炎症和自身免疫。这项研究的具体目的如下：i)确定氧化剂和PPAR？\γ在巨噬细胞编程中的正常作用及其与慢性肾衰患者潜在的吞噬功能缺陷和炎症介质过度产生的关系；ii)确定PPARγ激动剂在恢复CGD巨噬细胞功能中的作用；iii)确定PPARγ激动剂在逆转CGD中性粒细胞和巨噬细胞功能障碍中的替代机制(S)产生的氧化剂的作用。这项研究将在小鼠和人类CGD中性粒细胞和单核/巨噬细胞中进行，使用复杂的生化、遗传学和药理学方法。我们将使用一种明确的小鼠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，将i)阐明ROS产生缺陷和吞噬细胞功能错误之间的相互联系，以及ii)确定恢复的PPARγ信号是否以及如何逆转受损的泡沫化和炎症反应。一种新的假说可以解释慢性阻塞性肺疾病的持续性炎症反应以及通过PPARγ缓解炎症反应，这将支持一种新的治疗方法。这项研究旨在作为一种现有疗法的临床前试验，该疗法是PPARγ激动剂，可用于治疗慢性充血性心力衰竭患者。需要深入了解巨噬细胞编程和PPARγ信号在慢性萎缩性脑病和正常情况下识别和清除凋亡细胞的作用。这些发现也应该为其他炎症性疾病状态提供关键的洞察力，在这些状态下，巨噬细胞编程和对凋亡细胞的识别似乎存在缺陷。

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.