Neutrophil Nox2 controls mononuclear cell functions in inflammation; role in CGD

项目摘要/摘要 慢性肉芽肿性疾病(CGD)是一种罕见但毁灭性的疾病，具有已知的遗传异常。 吞噬细胞(白血球)氧化酶。除了免疫缺陷(无法对抗某些细菌 和真菌)，这种疾病的患者通常有复杂的和鲜为人知的炎性异常 病变表现为结肠炎、伤口愈合不良、阻塞性肉芽肿和自身免疫。重要的是 对于许多这些炎症性后果，缺乏明确适用和有效的治疗方法。 我们在人类X连锁CGD动物模型上的研究清楚地指出了炎症过程中的异常串扰 两种不同类型的吞噬细胞之间的过程，都带有突变的氧化酶：中性粒细胞(或 粒细胞)和单核巨噬细胞。具体地说，我们已经证明，尽管CGD中性粒细胞 无法控制单个核细胞的募集、成熟、炎性编程和处置 在炎症部位的吞噬细胞，直接引入正常的中性粒细胞能够恢复这些 活体内的活动和事件。因此，来自正常中性粒细胞的信号协调 单核巨噬细胞在正常发育和消退炎症的每一步。它是 假设识别这些由正常中性粒细胞提供的信号可以提供新的治疗方法 战略。采用小鼠模型和中性粒细胞及其产物的过继转移以及细胞共培养 培养实验(体外)，这一建议旨在定义异常的机制 CGD中的单核吞噬细胞行为以及CGD中性粒细胞缺乏的精确过程 通过添加正常的中性粒细胞来克服。对这些的定义有望带来新的方法来 治疗CGD和可能的其他慢性炎症情况。 。

Project Summary / Abstract Chronic granulomatous disease (CGD) is a rare, but devastating, disease with known genetic abnormalities in the phagocyte (white blood cell) oxidase. In addition to immunodeficiency (the inability to fight certain bacteria and fungi), patients with this disease often have complex and poorly understood abnormalities in inflammatory processes manifest as colitis, poor wound healing, obstructing granuloma, and autoimmunity. Importantly, there is a lack of clearly applicable and effective treatments for many of these inflammatory consequences. Our studies in an animal model of human X-linked CGD clearly point to abnormal crosstalk during inflammatory processes between two different types of phagocytes, both with the mutated oxidase: neutrophils (or granulocytes) and mononuclear phagocytes. Specifically, we have shown that whereas CGD neutrophils were unable control the recruitment, maturation, inflammatory programming and disposal of the mononuclear phagocytes at sites of inflammation, the direct introduction of normal neutrophils was able to restore these activities and events in vivo. As such, signals from normal neutrophils orchestrate the activities of the mononuclear phagocytes at each step in the normal development and resolution of inflammation. It is hypothesized that identifying these signals provided by normal neutrophils could provide new therapeutic strategies. Using the murine model and adoptive transfers of neutrophils and their products as well as cell co- culture experiments (ex vivo), this proposal aims to define the mechanisms underlying the abnormal mononuclear phagocyte behavior in CGD and the precise processes lacking in CGD neutrophils that are overcome by the addition of normal neutrophils. Defining these is expected to lead to novel approaches to treatment of CGD and possibly other chronic inflammatory conditions. .