Cytosolic Phospholipase A2α Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection
2017
Pulmonary infection by Streptococcus pneumoniae is characterized by a robust alveolar infiltration of neutrophils (polymorphonuclear cells or 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 α) 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 α dramatically reduced lung inflammation in mice upon high-dose pulmonary challenge with S. pneumoniae . The cPLA 2 α-deficient mice also suffered no bacteremia and survived a pulmonary challenge that was lethal to wild type mice. Our data suggest that cPLA 2 α plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection and is required for lethal systemic infection following S. pneumoniae lung challenge.
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