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

Abstract

Pulmonary infection by <i>Streptococcus pneumoniae</i> 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 A₃ (HXA₃) from arachidonic acid (AA), promotes acute pulmonary inflammation and systemic infection after lung challenge with <i>S. pneumoniae</i> As phospholipase A₂ (PLA₂) promotes the release of AA, we investigated the role of PLA₂ in local and systemic disease during <i>S. pneumoniae</i> infection. The group IVA cytosolic isoform of PLA₂ (cPLA₂α) was activated upon <i>S. pneumoniae</i> infection of cultured lung epithelial cells and was critical for AA release from membrane phospholipids. Pharmacological inhibition of this enzyme blocked <i>S. pneumoniae</i>-induced PMN transepithelial migration <i>in vitro</i> Genetic ablation of the cPLA₂ isoform cPLA₂α dramatically reduced lung inflammation in mice upon high-dose pulmonary challenge with <i>S. pneumoniae</i> The cPLA₂α-deficient mice also suffered no bacteremia and survived a pulmonary challenge that was lethal to wild-type mice. Our data suggest that cPLA₂α plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection and is required for lethal systemic infection following <i>S. pneumoniae</i> lung challenge.