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

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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. .