Interferon-γ Production by Neutrophils during Bacterial Pneumonia in Mice

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Abstract
Rationale: Neutrophils are usually the first circulating leukocytes to respond during bacterial pneumonia. Their expression of oxidants, proteases, and other mediators present in granules is well documented, but their ability to produce mediators through transcription and translation after migration to an inflammatory site has been appreciated only more recently. Interferon (IFN)-gamma is a cytokine with many functions important in host defense and immunity. Objectives: To examine the expression and function of IFN-gamma in bacterial pneumonias. Methods: IFN-gamma mRNA and protein were measured in digests of mouse lungs with 24-hour bacterial pneumonia. Bacterial clearance was studied with IFN-gamma-deficient mice. Measurements and Main Results: Streptococcus pneumoniae and Staphylococcus aureus each induce expression of IFN-gamma mRNA and protein by neutrophils by 24 hours. Only neutrophils that have migrated into pneumonic tissue produce IFN-gamma. Deficiency of Hck/Fgr/Lyn, Rac2, or gp91(phox) prevents IFN-gamma production. IFN-gamma enhances bacterial clearance and is required for formation of neutrophil extracellular traps. In contrast, Pseudomonas aeruginosa and Escherichia coli induce production of IFN-gamma mRNA but not protein. During pneumonia induced by E. coli but not S. pneumoniae, neutrophils produce microRNAs that target the 3' untranslated region of the IFN-gamma gene. Conclusions: S. pneumoniae and S. aureus, but not P. aeruginosa and E. coli, induce emigrated neutrophils to produce IFN-gamma within 24 hours. Hck/Fgr/Lyn, Rac2, and NADPH oxidase are required for IFN-gamma production. IFN-gamma facilitates bacterial clearance at least in part through regulating formation of neutrophil extracellular traps. Differential expression by neutrophils of microRNAs that target the 3' untranslated region of the IFN-gamma gene may contribute to the pathogen-specific regulation of translation.