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. TGF), 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 PPAR? , 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 PPAR? ? in macrophage programming and their relationship to underlying deficient efferocytosis and over-production of inflammatory mediators in CGD, ii) define the actions of PPAR? agonists in the restoration of CGD macrophage functioning and iii) define the role of oxidants produced by alternative mechanism(s) during PPAR? 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 PPAR? signaling reverses impaired efferocytosis and inflammatory responses. A new hypothesis to explain the persistent inflammatory response in CGD along with its mitigation through PPAR? will support a novel therapeutic approach. This investigation is intended to be a pre-clinical trial of an existing therapy, PPAR? agonists, available for treatment of CGD patients. A thorough understanding of macrophage programming and PPAR? 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.

Public Health Relevance

Relevance to Public Health 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 PPAR? signaling result in deficient anti- inflammatory 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 PPAR? signaling that are awry in CGD, and importantly, define PPAR? as an emerging therapeutic target amenable to pharmacologic restoration for treatment of this disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI110408-05
Application #
9416907
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Voulgaropoulou, Frosso
Project Start
2014-02-15
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2020-01-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Mould, Kara J; Barthel, Lea; Mohning, Michael P et al. (2017) Cell Origin Dictates Programming of Resident versus Recruited Macrophages during Acute Lung Injury. Am J Respir Cell Mol Biol 57:294-306
Gibbings, Sophie L; Thomas, Stacey M; Atif, Shaikh M et al. (2017) Three Unique Interstitial Macrophages in the Murine Lung at Steady State. Am J Respir Cell Mol Biol 57:66-76
Frasch, S Courtney; McNamee, Eóin N; Kominsky, Douglas et al. (2016) G2A Signaling Dampens Colitic Inflammation via Production of IFN-?. J Immunol 197:1425-34
Janssen, William J; Bratton, Donna L; Jakubzick, Claudia V et al. (2016) Myeloid Cell Turnover and Clearance. Microbiol Spectr 4:
Desch, A Nicole; Gibbings, Sophie L; Goyal, Rajni et al. (2016) Flow Cytometric Analysis of Mononuclear Phagocytes in Nondiseased Human Lung and Lung-Draining Lymph Nodes. Am J Respir Crit Care Med 193:614-26
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
Gibbings, Sophie L; Goyal, Rajni; Desch, A Nicole et al. (2015) Transcriptome analysis highlights the conserved difference between embryonic and postnatal-derived alveolar macrophages. Blood 126:1357-66
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
Eltzschig, Holger K; Bratton, Donna L; Colgan, Sean P (2014) Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat Rev Drug Discov 13:852-69
Caceres, Silvia M; Malcolm, Kenneth C; Taylor-Cousar, Jennifer L et al. (2014) Enhanced in vitro formation and antibiotic resistance of nonattached Pseudomonas aeruginosa aggregates through incorporation of neutrophil products. Antimicrob Agents Chemother 58:6851-60