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

Abstract

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 ␣) 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 ␣ dramatically reduced lung inflammation in mice upon high-dose pulmonary challenge with S. pneumoniae. The cPLA 2 ␣-deficient mice also suffered no bacteremia and survived a pulmonary challenge that was lethal to wild-type mice. Our data suggest that cPLA 2 ␣ plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection and is required for lethal systemic infection following S. pneumoniae lung challenge.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…This off-target effect, implicating a serine hydrolase in regulation of ER calcium release, highlights the importance of careful dose-response studies with pyrrophenone to study GIVA cPLA 2 function. The role of GIVA cPLA 2 in local and systemic disease during S. pneumonia infection was investigated and it was demonstrated that pharmacological inhibition of GIVA cPLA 2 by RSC-3388 blocked Streptococcus pneumoniae-induced polymorphonuclear cells transepithelial migration in vitro [29]. Those results suggest that the enzyme plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection.…”

Arachidonic Acid Stress Impacts Pneumococcal Fatty Acid Homeostasis

“…Fatty acids play important roles in phagocytic cells, where omega-6 fatty acids, such as AA, are associated with enhanced phagocytic functionality by mechanisms such as improved phagolysosome maturation and greater bacterial killing (Anes et al, 2003 ; Jordao et al, 2008 ). Further, the release of AA from membrane phospholipids is critical for the production of the neutrophil chemoattractant, hepoxillin A 3 , which has key roles in systemic pneumococcal infections (Bhowmick et al, 2017 ). Fatty acids have also been proposed to target phagocytosed pathogens within macrophages through fusion of the phagolysosome with lipid bodies containing high concentrations of fatty acids (Adolph et al, 2012 ; Caire-Brändli et al, 2014 ).…”

“…Consistent with this inference, host-produced long chain-polyunsaturated fatty acids (LC-PUFAs; ≥20 carbons and ≥2 double bonds) often display greater antibacterial potential than medium/short chain saturated and monounsaturated fatty acids (≥18 carbons and 0 or 1 double bonds), which are produced by both the host and bacteria (Desbois and Smith, 2010 ). The omega-6 LC-PUFA arachidonic acid (20:4n-6) is known as a precursor for the immunomodulatory prostaglandins (Bhowmick et al, 2013 , 2017 ), but it is also one of the most abundant broad spectrum antimicrobial fatty acids, affecting bacteria, viruses and fungi (Kohn et al, 1980 ; Zheng et al, 2005 ; Ells et al, 2009 ).…”

Genetic inactivation of the phospholipase A2activity of peroxiredoxin 6 in mice protects against LPS-induced acute lung injury

“…Other PLA 2 enzymes such as cytosolic PLA 2 and type II secretory PLA 2 have previously been implicated in the progression of sepsis-induced ALI (9,41,49,51). Although their precise roles in ALI remain elusive, their effects derive mainly from the liberation of arachidonic acid for the generation of inflammatory mediators (4,42,54). Of note, aiPLA 2 , in contrast to these other PLA 2 enzymes, does not show a substrate preference for arachidonic acid-containing phospholipids (1,32).…”