IFN-γ targets macrophage-mediated immune responses toward Staphylococcus aureus

Mallary C. Greenlee-Wacker, William M. Nauseef

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Infections, especially with Staphylococcus 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-1b production by macrophages. IFN-g 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-g improves responsiveness of macrophages to SA and provides insights into the mechanism of the clinical benefits of IFN-γ.

Original languageEnglish
Pages (from-to)751-758
Number of pages8
JournalJournal of Leukocyte Biology
Volume101
Issue number3
DOIs
StatePublished - Mar 2017

Keywords

  • CGD
  • Efferocytosis
  • Inflammation
  • MRSA
  • Neutrophil

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