Prostaglandin E<sub>2</sub> Regulates Activation of Mouse Peritoneal Macrophages by <b><i>Staphylococcus aureus</i></b> through Toll-Like Receptor 2, Toll-Like Receptor 4, and NLRP3 Inflammasome Signaling

Abstract

Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>), an essential endogenous lipid mediator for normal physiological functions, can also act as an inflammatory mediator in pathological conditions. We determined whether <i>Staphylococcus aureus</i> lipoproteins are essential for inducing PGE<sub>2</sub> secretion by immune cells and whether pattern recognition receptors mediate this process. PGE<sub>2</sub> levels secreted by mouse peritoneal macrophages infected with the <i>S. aureus</i> isogenic mutant, <i>lgt</i>::ermB (Δ<i>lgt</i>; deficient in lipoprotein maturation), decreased compared with those from macrophages infected with wild-type (WT) <i>S. aureus</i>. Experiments using toll-like receptors 2 (TLR2)-deficient, TLR4-deficient, and NLRP3-deficient mice indicated that these 3 proteins are involved in macrophage PGE<sub>2</sub> secretion in response to <i>S. aureus</i>, and lipoproteins were essential for <i>S. aureus</i> invasion and survival within macrophages. Inhibition of endogenous PGE<sub>2</sub> synthesis had no effect on bacterial invasion. Exogenous PGE<sub>2</sub> inhibited phagocytosis in the WT <i>S. aureus</i> and its isogenic mutant but increased intracellular killing accompanied by enhanced IL-1β secretion. Our data demonstrate that <i>S. aureus</i> can induce macrophage TLR/mitogen-activated protein kinase/NF-κB signaling and that PGE<sub>2</sub> treatment upregulates NLRP3/caspase-1 signaling activation. Thus, macrophage PGE<sub>2</sub> secretion after <i>S. aureus</i> infection depends on bacterial lipoprotein maturation and macrophage receptors TLR2, TLR4, and NLRP3. Moreover, exogenous PGE<sub>2</sub> regulates <i>S. aureus</i>-induced macrophage activation through TLRs and NLRP3 inflammasome signaling.