Neutrophil and Macrophage NADPH Oxidase 2 Differentially Control Responses to Inflammation and to Aspergillus fumigatus in Mice [INFECTIOUS DISEASE AND HOST RESPONSE]

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.

Footnotes

This work was supported by grants from the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (R01HL140837 to M.C.D.), NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR072212 to M.C.D.), the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (M.C.D.), National Institute of Allergy and Infectious Diseases (5R01AI150669-01A1 to N.P.K.), National Institute of General Medical Sciences (R35GM118027-01 to A.H.), and an NIH Shared Instrumentation Grant (S10 RR027552).

The online version of this article contains supplemental material.

Abbreviations used in this article:

BALbronchoalveolar lavageCGDchronic granulomatous diseaseDAMPdamage-associated molecular patternDHRdihydrorhodamineGMSGomori methenamine silverhpihours postinfectionINintranasalIPAinvasive pulmonary aspergillosisLTB4leukotriene B4NOX2NADPH oxidase 2ROSreactive oxygen speciesWTwild-typeWUSMWashington University School of Medicine in St. LouisReceived July 26, 2022.Accepted September 8, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.

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