Cytosolic Phospholipase A2α Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection

Pulmonary infection by Streptococcus pneumoniae is characterized by a robust alveolar infiltration of neutrophils (polymorphonuclear cells [PMNs]) that can promote systemic spread of the infection if not resolved. We previously showed that 12-lipoxygenase (12-LOX), which is required to generate the PMN chemoattractant hepoxilin A(3) (HXA(3)) from arachidonic acid (AA), promotes acute pulmonary inflammation and systemic infection after lung challenge with S. pneumoniae. As phospholipase A(2) (PLA(2)) promotes the release of AA, we investigated the role of PLA(2) in local and systemic disease during S. pneumoniae infection. The group IVA cytosolic isoform of PLA(2) (cPLA(2)alpha) was activated upon S. pneumoniae infection of cultured lung epithelial cells and was critical for AA release from membrane phospholipids. Pharmacological inhibition of this enzyme blocked S. pneumoniae-induced PMN transepithelial migration in vitro. Genetic ablation of the cPLA(2) isoform cPLA(2)alpha dramatically reduced lung inflammation in mice upon high-dose pulmonary challenge with S. pneumoniae. The cPLA(2)alpha-deficient mice also suffered no bacteremia and survived a pulmonary challenge that was lethal to wild-type mice. Our data suggest that cPLA(2)alpha plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection and is required for lethal systemic infection following S. pneumoniae lung challenge.