Mechanisms of Interferon-γ Production by Neutrophils and Its Function during Streptococcus pneumoniae Pneumonia

Bacterial pneumonia is a common public health problem associated with significant mortality, morbidity, and cost. Neutrophils are usually the earliest leukocytes to respond to bacteria in the lungs. Neutrophils rapidly sequester in the pulmonary microvasculature and migrate into the lung parenchyma and alveolar spaces, where they perform numerous effector functions for host defense. Previous studies showed that migrated neutrophils produce IFN-gamma early during pneumonia induced by Streptococcus pneumoniae and that early production of IFN-gamma regulates bacterial clearance. IFN-gamma production by neutrophils requires Rac2, Hck/Lyn/Fgr Src family tyrosine kinases, and NADPH oxidase. Our current studies examined the mechanisms that regulate IFN-gamma production by lung neutrophils during acute S. pneumoniae pneumonia in mice and its function. We demonstrate that IFN-gamma production by neutrophils is a tightly regulated process that does not require IL-12. The adaptor molecule MyD88 is critical for IFN-gamma production by neutrophils. The guanine nucleotide exchange factor CalDAG-GEFI modulates IFN-gamma production. The CD11/CD18 complex, CD44, Toll-like receptors 2 and 4, TRIF, and Nrf2 are not required for IFN-gamma production by neutrophils. The recently described neutrophil-dendritic cell hybrid