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

项目概要/摘要 慢性肉芽肿病（CGD）是一种罕见的，但破坏性的疾病，已知的遗传异常， 吞噬细胞（白色血细胞）氧化酶。除了免疫缺陷（无法对抗某些细菌）之外， 和真菌），这种疾病的患者往往有复杂的和了解不多的异常，炎症 过程表现为结肠炎、伤口愈合不良、阻塞性肉芽肿和自身免疫。重要的是， 对于许多这些炎性后果缺乏明确适用和有效的治疗。 我们在人类X连锁CGD动物模型中的研究清楚地指出，在炎症过程中， 两种不同类型的吞噬细胞之间的过程，都与突变的氧化酶：中性粒细胞（或 粒细胞）和单核吞噬细胞。具体来说，我们已经表明，虽然CGD中性粒细胞是 无法控制单核细胞的募集、成熟、炎症编程和处置， 在炎症部位的吞噬细胞，正常中性粒细胞的直接引入能够恢复这些 活动和事件在体内。因此，来自正常嗜中性粒细胞的信号协调了 单核吞噬细胞在炎症的正常发展和消退的每一步。是 假设识别正常中性粒细胞提供的这些信号可以提供新的治疗方法， 战略布局使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（离体），该建议旨在定义异常的潜在机制， CGD中单核吞噬细胞的行为和CGD中性粒细胞缺乏的精确过程， 通过增加正常的中性粒细胞来克服。对这些问题的界定有望导致新的方法， 治疗CGD和可能的其他慢性炎性病症。 .

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. .