Type III interferons restrict neutrophil activity in response to Staphylococcus aureus

Abstract

Abstract Staphylococcus aureus is an important human pathogen, in particular the methicillin resistant S. aureus (MRSA) strain USA300 that is epidemic in the United States. Type III interferons (IFN-λ) signal through the IL-28 receptor (IFNLR) located on epithelial cells and neutrophils. Neutrophil-mediated killing is a crucial defence system against S. aureus. Compared to WT mice, Ifnlr−/− mice had significantly improved clearance of S. aureus from the airway and lung tissue (>90%; P<0.001) following a 24-hour infection. In a mortality model of infection, all Ifnlr−/− mice survived, whereas 75% of WT mice succumbed to infection (P<0.05). Despite a lack of difference in neutrophil recruitment to the airway in WT and Ifnlr−/− mice in response to S. aureus, Ifnlr−/− infected mice showed a significant increase in the neutrophil related cytokine G-CSF (38%; P<0.05). Moreover, expression of the neutrophil surface markers, Ly6C and Ly6G, were higher (39% and 20%, respectively; P<0.01) on infected Ifnlr−/− neutrophils compared to WT infected mice. Neutrophils isolated from Ifnlr−/− mice compared to WT neutrophils also displayed a 2-fold increase in MPO activity (peroxidation) (p<0.05) and a 2.1-fold increase in Ca2+ flux when compared to WT neutrophils (P<0.001), while WT neutrophils stimulated with purified IFN-λ displayed a 0.5-fold decrease in Ca2+ flux (p<0.005). In addition, stimulation of WT neutrophils with purified IFN-λ led to a 2-fold decrease of their S. aureus killing capacity (P<0.05). Controlling neutrophil recruitment and activation is important to provide a balanced response to infection. Our data suggests that type III IFN signalling can impair neutrophil activation and their killing capacity in response to S. aureus.