Eicosanoid-mediated proinflammatory activity of Pseudomonas aeruginosa ExoU

Abstract

SummaryAs Pseudomonas aeruginosa ExoU possesses two functional blocks of homology to calcium-independent (iPLA 2 ) and cytosolic phospholipase A 2 (cPLA 2 ), we addressed the question whether it would exhibit a proinflammatory activity by enhancing the synthesis of eicosanoids by host organisms. Endothelial cells from the HMEC-1 line infected with the ExoU-producing PA103 strain exhibited a potent release of arachidonic acid (AA) that could be significantly inhibited by methyl arachidonyl fluorophosphonate (MAFP), a specific PLA 2 inhibitor, as well as significant amounts of the cyclooxygenase (COX)-derived prostaglandins PGE 2 and PGI 2 . Cells infected with an isogenic mutant defective in ExoU synthesis did not differ from noninfected cells in the AA release and produced prostanoids in significantly lower concentrations. Infection by PA103 induced a marked inflammatory response in two different in vivo experimental models. Inoculation of the parental bacteria into mice footpads led to an early increase in the infected limb volume that could be significantly reduced by inhibitors of both COX and lipoxygenase (ibuprofen and NDGA respectively). In an experimental respiratory infection model, bronchoalveolar lavage (BAL) from mice instilled with 10 4 cfu of PA103 exhibited a marked influx of inflammatory cells and PGE 2 release that could be significantly reduced by indomethacin, a non-selective COX inhibitor. Our results suggest that ExoU may contribute to P. aeruginosa pathogenesis by inducing an eicosanoid-mediated inflammatory response of host organisms.

Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX‐2

“…A recent study by Saliba et al [35] showed that ExoU modulates the production of eicosonoid mediators by endothelial cells, favoring the inflammatory response associated with P. aeruginosa infection. The present study suggests that ExoU and ExoT may also be directly involved in the induction of COX-2.…”

Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators

“…M. tuberculosis can also inhibit the formation of the proinflammatory lipid LTB 4 , further shifting the host lipid environment toward an antiinflammatory state (24). P. aeruginosa produces the 15-lipoxygenase LoxA (25,26), as well as the phospholipase ExoU (27), both of which can potentially generate antiinflammatory signals. However, unlike many airway pathogens, P. aeruginosa survives in a hyperinflammatory environment, particularly in the context of chronic lung disease (2).…”

Multiple Roles of Phospholipase A2during Lung Infection and Inflammation

“…ExoU is incapable of acting on the extracellular surface because interaction with the intracellular enzyme superoxide dismutase 1 is required for PLA 2 activity (105). In the lung, ExoU is thought to target epithelial cells, endothelial cells, and macrophages (100,117).…”