Role of NADPH Oxidase in Regulating Inflammation

描述（由申请人提供）：慢性肉芽肿病（CGD）是一种罕见的NADPH氧化酶复合物遗传性疾病，吞噬细胞在产生超氧阴离子和下游活性氧化中间体（roi）方面存在缺陷。CGD的特点是复发性危及生命的细菌和真菌感染以及过度的炎症反应。CGD的过度炎症不仅仅是未解决的感染的结果，而是炎症控制的内在缺陷的结果。利用基因工程小鼠模型，我们已经确定了NADPH氧化酶下调炎症的两种可能机制。首先，我们已经证明NADPH氧化酶直接或间接下调NF-？体外和体内B活化。其次，NADPH氧化酶激活核红细胞2 p45相关因子2 (Nrf2)，这是一个具有抗炎和抗肿瘤特性的关键氧化还原敏感途径。我们的具体目标集中在与NADPH氧化酶如何下调炎症相关的三个相互关联的问题上：具体目标1：验证NADPH氧化酶通过氧化还原敏感抑制IKK2活性来减弱NF-：激活的假设。目的2：探讨NADPH氧化酶与Nrf2在炎症调节中的相互作用。具体目的3：验证中性粒细胞中NADPH氧化酶衍生的roi会调节NF-?？B和Nrf2信号在邻近细胞中的表达，并减少CGD小鼠过继转移后的炎症。公共卫生相关性：慢性肉芽肿病（CGD）是一种罕见的NADPH氧化酶遗传性疾病，NADPH氧化酶是宿主防御微生物病原体的关键成分。我们的建议将评估NADPH氧化酶调节炎症的机制，这将对我们理解CGD很重要，并且将广泛与病理条件相关，如炎症性疾病和癌症。

DESCRIPTION (provided by applicant): Chronic granulomatous disease (CGD) is a rare inherited disorder of the NADPH oxidase complex in which phagocytes are defective in generating superoxide anion and downstream reactive oxidant intermediates (ROIs). CGD is characterized by recurrent life-threatening bacterial and fungal infections and by excessive inflammatory responses. Excessive inflammation in CGD is not solely the result of unresolved infection, but results from an intrinsic defect in the control of inflammation. Using genetically engineered mouse models, we have identified two possible mechanisms by which NADPH oxidase may downregulate inflammation. First, we have shown that NADPH oxidase, directly or indirectly, downregulates NF-?B activation in vitro and in vivo. Second, NADPH oxidase activates nuclear erythroid 2 p45 related factor 2 (Nrf2), a key redox-sensitive pathway with anti- inflammatory and anti-neoplastic properties. Our specific aims are focused on three inter-related questions related to how NADPH oxidase downregulates inflammation: Specific aim 1: To test the hypothesis that NADPH oxidase attenuates NF-: activation by redox-sensitive suppression of IKK2 activity. Specific aim 2: To evaluate the interaction of NADPH oxidase and Nrf2 in regulating inflammation. Specific aim 3: To test the hypothesis that NADPH oxidase-derived ROIs from neutrophils will modulate NF-??B and Nrf2 signaling in neighboring cells and reduce inflammation in CGD mice following adoptive transfer. Public Health Relevance: Chronic granulomatous disease (CGD) is a rare inherited disorder of the he NADPH oxidase, a critical component of host defense against microbial pathogens. Our proposal will evaluate mechanisms by which NADPH oxidase regulates inflammation that will be important to our understanding of CGD, and will be broadly relevant to pathologic conditions, such as inflammatory disorders and cancer.