title: IFN-γ targets macrophage-mediated immune responses towardStaphylococcus aureus.
abstract: Infections, especially withStaphylococcus aureus(SA), commonly cause morbidity and mortality in patients with chronic granulomatous disease (CGD), a condition characterized by a defective phagocyte oxidase. IFN-γ reduces the frequency and consequences of infection in CGD by mechanisms that remain unknown. As IFN-γ promotes bacterial killing, efferocytosis of effete polymorphonuclear neutrophils (PMN), and cytokine production in macrophages-the same macrophage effector functions that are impaired in response to SA-we hypothesized that IFN-γ may reverse these defects and thereby, augment macrophage control of SA during infection. IFN-γ primed activation of the NADPH oxidase in a time-dependent manner, enhanced killing of ingested SA independent of any effects on phagocytosis, and increased binding of SA-laden neutrophils (PMN-SA) to macrophages. However, IFN-γ did not increase the percentage of apoptotic PMN or PMN-SA internalized by macrophages. Under conditions in which viable SA were eliminated, PMN-SA primed the inflammasome for subsequent activation by silica but did not induce IL-1β production by macrophages. IFN-γ enhanced IL-6 production in response to SA or PMN-SA but did not increase inflammasome activation in response to either agonist. In summary, IFN-γ augmented direct killing of SA by macrophages, promoted engagement of PMN-SA, and enhanced macrophage-mediated cytokine responses that could collectively augment control of SA infection. Together, these findings support the hypothesis that IFN-γ improves responsiveness of macrophages to SA and provides insights into the mechanism of the clinical benefits of IFN-γ.
authors.affiliation: Biology Department, Central Michigan University, Mount Pleasant, Michigan, USA; and.
authors.forename: Mallary C
authors.initials: MC
authors.lastname: Greenlee-Wacker
authors.affiliation: Inflammation Program and Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, and Veterans Affairs Medical Center, Iowa City, Iowa, USA william-nauseef@uiowa.edu.
authors.forename: William M
authors.initials: WM
authors.lastname: Nauseef
mesh_terms: D002450:Cell Communication / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D050296:Microbial Viability / Q000187:drug effects; D019255:NADPH Oxidases / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000276:immunology*
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D007371:Interferon-gamma; D019255:NADPH Oxidases
keywords: CGD; MRSA; efferocytosis; inflammation; neutrophil