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. TGFβ), 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 PPARγ 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 therapeutic intervention 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.
Aside from problems fighting certain infections, patients with Chronic Granulomatous Disease (CGD) also suffer from exaggerated inflammation, e.g. poor wound healing, obstructing granulomas, colitis and autoimmunity. In CGD, the lack of phagocyte oxidants and deficient PPARγsignaling result in deficient antiinflammatory controls necessary for regulating leukocyte recruitment, orchestrating clearance of dying cells, and suppressing inflammatory mediator production, all key to resolving inflammation. This proposal seeks to define the interconnections of oxidants and PPARγsignaling that are awry in CGD, and importantly, define PPARγas an emerging therapeutic target amenable to pharmacologic restoration for treatment of this disorder.
| Fernandez-Boyanapalli, Ruby F; Falcone, Emilia Liana; Zerbe, Christa S et al. (2015) Impaired efferocytosis in human chronic granulomatous disease is reversed by pioglitazone treatment. J Allergy Clin Immunol 136:1399-1401.e3 |
| Fernandez-Boyanapalli, Ruby F; Frasch, S Courtney; Thomas, Stacey M et al. (2015) Pioglitazone restores phagocyte mitochondrial oxidants and bactericidal capacity in chronic granulomatous disease. J Allergy Clin Immunol 135:517-527.e12 |
| Redente, Elizabeth F; Keith, Rebecca C; Janssen, William et al. (2014) Tumor necrosis factor-? accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages. Am J Respir Cell Mol Biol 50:825-37 |
| Henson, Peter M; Bratton, Donna L (2013) Antiinflammatory effects of apoptotic cells. J Clin Invest 123:2773-4 |
| Fernandez-Boyanapalli, Ruby; Goleva, Elena; Kolakowski, Christena et al. (2013) Obesity impairs apoptotic cell clearance in asthma. J Allergy Clin Immunol 131:1041-7, 1047.e1-3 |
| Frasch, S Courtney; Fernandez-Boyanapalli, Ruby F; Berry, Karin A Zemski et al. (2013) Neutrophils regulate tissue Neutrophilia in inflammation via the oxidant-modified lipid lysophosphatidylserine. J Biol Chem 288:4583-93 |
| Xiong, Weipeng; Frasch, S Courtney; Thomas, Stacey M et al. (2013) Induction of TGF-?1 synthesis by macrophages in response to apoptotic cells requires activation of the scavenger receptor CD36. PLoS One 8:e72772 |
| Frasch, S Courtney; Bratton, Donna L (2012) Emerging roles for lysophosphatidylserine in resolution of inflammation. Prog Lipid Res 51:199-207 |
| Frasch, S Courtney; Fernandez-Boyanapalli, Ruby F; Berry, Karin Zemski et al. (2011) Signaling via macrophage G2A enhances efferocytosis of dying neutrophils by augmentation of Rac activity. J Biol Chem 286:12108-22 |
| Korns, Darlynn; Frasch, S Courtney; Fernandez-Boyanapalli, Ruby et al. (2011) Modulation of macrophage efferocytosis in inflammation. Front Immunol 2:57 |
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