Prostaglandin E2 Regulates Activation of Mouse Peritoneal Macrophages by Staphylococcus aureus through Toll-Like Receptor 2, Toll-Like Receptor 4, and NLRP3 Inflammasome Signaling

Abstract

Prostaglandin E₂ (PGE₂), an essential endogenous lipid mediator for normal physiological functions, can also act as an inflammatory mediator in pathological conditions. We determined whether Staphylococcus aureus lipoproteins are essential for inducing PGE₂ secretion by immune cells and whether pattern recognition receptors mediate this process. PGE₂ levels secreted by mouse peritoneal macrophages infected with the S. aureus isogenic mutant, lgt::ermB (Δlgt; deficient in lipoprotein maturation), decreased compared with those from macrophages infected with wild-type (WT) S. aureus. Experiments using toll-like receptors 2 (TLR2)-deficient, TLR4-deficient, and NLRP3-deficient mice indicated that these 3 proteins are involved in macrophage PGE₂ secretion in response to S. aureus, and lipoproteins were essential for S. aureus invasion and survival within macrophages. Inhibition of endogenous PGE₂ synthesis had no effect on bacterial invasion. Exogenous PGE₂ inhibited phagocytosis in the WT S. aureus and its isogenic mutant but increased intracellular killing accompanied by enhanced IL-1β secretion. Our data demonstrate that S. aureus can induce macrophage TLR/mitogen-activated protein kinase/NF-κB signaling and that PGE₂ treatment upregulates NLRP3/caspase-1 signaling activation. Thus, macrophage PGE₂ secretion after S. aureus infection depends on bacterial lipoprotein maturation and macrophage receptors TLR2, TLR4, and NLRP3. Moreover, exogenous PGE₂ regulates S. aureus-induced macrophage activation through TLRs and NLRP3 inflammasome signaling.