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Updated: Aug 20, 2025
Assessing Anti-fungal Activity of Isolated Alveolar Macrophages by Confocal Microscopy
Published on: July 9, 2014
Neutrophil and Macrophage NADPH Oxidase 2 Differentially Control Responses to Inflammation and to Aspergillus
Rachel A Idol1, Sourav Bhattacharya1, Guangming Huang1
1Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO.
Abstract:
Aspergillus fumigatus is an important opportunistic fungal pathogen and causes invasive pulmonary aspergillosis in conditions with compromised innate antifungal immunity, including chronic granulomatous disease, which results from inherited deficiency of the superoxide-generating leukocyte NADPH oxidase 2 (NOX2). Derivative oxidants have both antimicrobial and immunoregulatory activity and, in the context of A. fumigatus, contribute to both fungal killing and dampening inflammation induced by fungal cell walls. As the relative roles of macrophage versus neutrophil NOX2 in the host response to A. fumigatus are incompletely understood, we studied mice with conditional deletion of NOX2. When NOX2 was absent in alveolar macrophages as a result of LysM-Cre-mediated deletion, germination of inhaled A. fumigatus conidia was increased. Reducing NOX2 activity specifically in neutrophils via S100a8 (MRP8)-Cre also increased fungal burden, which was inversely proportional to the level of neutrophil NOX2 activity. Moreover, diminished NOX2 in neutrophils synergized with corticosteroid immunosuppression to impair lung clearance of A. fumigatus. Neutrophil-specific reduction in NOX2 activity also enhanced acute inflammation induced by inhaled sterile fungal cell walls. These results advance understanding into cell-specific roles of NOX2 in the host response to A. fumigatus. We show that alveolar macrophage NOX2 is a nonredundant effector that limits germination of inhaled A. fumigatus conidia. In contrast, reducing NOX2 activity only in neutrophils is sufficient to enhance inflammation to fungal cell walls as well as to promote invasive A. fumigatus. This may be relevant in clinical settings with acquired defects in NOX2 activity due to underlying conditions, which overlap risk factors for invasive aspergillosis.
Insights
Alveolar macrophage NADPH oxidase 2 (NOX2) limits fungal germination, while neutrophil NOX2 controls inflammation and fungal clearance. This clarifies NOX2
Area of Science:
- Immunology
- Mycology
- Cell Biology
Background:
- Aspergillus fumigatus causes invasive pulmonary aspergillosis in immunocompromised individuals.
- Leukocyte NADPH oxidase 2 (NOX2) is crucial for innate antifungal immunity.
- The distinct roles of macrophage and neutrophil NOX2 in A. fumigatus response are unclear.
Purpose of the Study:
- To investigate the cell-specific functions of NOX2 in host defense against A. fumigatus.
- To determine the impact of NOX2 deficiency in alveolar macrophages and neutrophils.
Main Methods:
- Utilized genetically modified mice with conditional deletion of NOX2 in specific immune cells (alveolar macrophages and neutrophils).
- Assessed fungal burden, conidial germination, and inflammatory responses following A. fumigatus inhalation.
- Examined the synergistic effects of NOX2 deficiency and corticosteroid immunosuppression.
Main Results:
- Absence of NOX2 in alveolar macrophages increased A. fumigatus conidial germination.
- Reduced NOX2 activity in neutrophils correlated with increased fungal burden and impaired lung clearance.
- Neutrophil-specific NOX2 reduction exacerbated inflammation induced by fungal cell walls and synergized with corticosteroids.
Conclusions:
- Alveolar macrophage NOX2 is essential for limiting the germination of inhaled A. fumigatus.
- Neutrophil NOX2 plays a critical role in controlling fungal burden, inflammation, and overall host defense against A. fumigatus.
- Findings highlight the importance of NOX2 in clinical settings with compromised immunity and risk factors for invasive aspergillosis.
