title: Monocyte- and macrophage-targeted NADPH oxidase mediates antifungal host defense and regulation of acute inflammation in mice.
abstract: Chronic granulomatous disease, an inherited disorder of the NADPH oxidase in which phagocytes are defective in the generation of superoxide anion and downstream reactive oxidant species, is characterized by severe bacterial and fungal infections and excessive inflammation. Although NADPH oxidase isoforms exist in several lineages, reactive oxidant generation is greatest in neutrophils, where NADPH oxidase has been deemed vital for pathogen killing. In contrast, the function and importance of NADPH oxidase in macrophages are less clear. Therefore, we evaluated susceptibility to pulmonary aspergillosis in globally NADPH oxidase-deficient mice versus transgenic mice with monocyte/macrophage-targeted NADPH oxidase activity. We found that the lethal inoculum was >100-fold greater in transgenic versus globally NADPH oxidase-deficient mice. Consistent with these in vivo results, NADPH oxidase in mouse alveolar macrophages limited germination of phagocytosed Aspergillus fumigatus spores. Finally, globally NADPH oxidase-deficient mice developed exuberant neutrophilic lung inflammation and proinflammatory cytokine responses to zymosan, a fungal cell wall-derived product composed principally of particulate β-glucans, whereas inflammation in transgenic and wild-type mice was mild and transient. Taken together, our studies identify a central role for monocyte/macrophage NADPH oxidase in controlling fungal infection and in limiting acute lung inflammation.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Grimm
authors.forename: R Robert
authors.initials: RR
authors.lastname: Vethanayagam
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Almyroudis
authors.forename: Carly G
authors.initials: CG
authors.lastname: Dennis
authors.forename: A Nazmul H
authors.initials: AN
authors.lastname: Khan
authors.forename: Anthony C
authors.initials: AC
authors.lastname: D'Auria
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Singel
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Davidson
authors.forename: Paul R
authors.initials: PR
authors.lastname: Knight
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hohl
authors.forename: Michael K
authors.initials: MK
authors.lastname: Mansour
authors.forename: Jatin M
authors.initials: JM
authors.lastname: Vyas
authors.forename: Marc
authors.initials: M
authors.lastname: Röhm
authors.forename: Constantin F
authors.initials: CF
authors.lastname: Urban
authors.forename: Tiina
authors.initials: T
authors.lastname: Kelkka
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.forename: Brahm H
authors.initials: BH
authors.lastname: Segal
mesh_terms: D000208:Acute Disease; D000818:Animals; D001228:Aspergillosis / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D001232:Aspergillus fumigatus / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000201:enzymology / Q000382:microbiology / Q000517:prevention & control; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000201:enzymology* / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology* / Q000382:microbiology; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015054:Zymosan / Q000494:pharmacology
chemical_list: D015054:Zymosan; D019255:NADPH Oxidases