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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 (?lgt; 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-1? secretion. Our data demonstrate that S. aureus can induce macrophage TLR/mitogen-activated protein kinase/NF-?B 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.

SUBMITTER: Wu J

PROVIDER: S-EPMC7098297 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Wu Jindi J Liu Bo B Mao Wei W Feng Shuang S Yao Yuan Y Bai Fan F Shen Yuan Y Guleng Amu A Jirigala Bayin B Cao Jinshan J

Journal of innate immunity 20190529 2

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), ...[more]

PMID: 31141808

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Project description:Inflammatory responses in the peritoneum contribute to peritoneal dialysis (PD)-associated peritoneal fibrosis. Results of our previous study showed that increased microsomal prostaglandin E synthase-1-mediated production of prostaglandin E2 (PGE2) contributed to peritoneal fibrosis. However, the role of its downstream receptor in the progression of peritoneal fibrosis has not been established. Here, we examined the role of PGE2 receptor 4 (EP4) in the development of peritoneal fibrosis. EP4 was significantly upregulated in peritoneal tissues of PD patients with ultrafiltration failure, along with the presence of an enhanced inflammatory response. In vitro experiments showed that exposure to high glucose concentrations enhanced EP4 expression in rat peritoneal mesothelial cells (RPMCs). High-glucose-induced expression of inflammatory cytokines (monocyte chemoattractant protein-1, tumour necrosis factor α, and interleukin 1β) was significantly reduced in RPMCs treated with ONO-AE3-208, an EP4 receptor antagonist. ONO-AE3-208 also significantly decreased the expression of extracellular matrix proteins induced by high glucose concentrations. Furthermore, ONO-AE3-208 blunted activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and phosphorylation of nuclear factor kappa B (NF-κB) (p-p65). To further investigate the functional role of EP4, ONO-AE3-208 was administrated for 4 weeks in a rat model of PD, the results of which showed that ONO-AE3-208 inhibited peritoneal fibrosis and improved peritoneal dysfunction. Additionally, inflammatory cytokines in the peritoneum of PD rats treated with ONO-AE3-208 were downregulated, in line with inhibition of the NLRP3 inflammasome and NF-κB phosphorylation. In conclusion, an EP4 antagonist reduced the development of peritoneal fibrosis, possibly by suppressing NLRP3 inflammasome- and p-p65-mediated inflammatory responses. Our findings suggest that an EP4 antagonist may be therapeutically beneficial for PD-associated peritoneal fibrosis.

Project description:IntroductionIn clinical settings, dairy cows are often attacked by pathogenic bacteria after delivery, especially Staphylococcus aureus (S. aureus). Neutrophils have long been regarded as essential for host defense against S. aureus. Prostaglandin E2 (PGE2) can additionally be used as an inflammatory mediator in pathological conditions to promote the repair of inflammatory injuries. However, whether S. aureus can promote the accumulation of PGE2 after the infection of neutrophils in cows and its mechanism remain unclear. Lipoprotein is an important immune bioactive ingredient of S. aureus.MethodsIn this study, the changes in neutrophils were monitored in dairy cows infected with wild-type S. aureus (SA113) and an S. aureus lipoprotein-deficient strain (Δlgt); meanwhile, we established whether pattern recognition receptors mediate this process and whether S. aureus lipoproteins are necessary for causing the release of PGE2 from cow neutrophils.ResultsThe results showed that Δlgt was less effective than SA113 in inducing the production of IL-1β, IL-6, IL-8, IL-10, and PGE2 within neutrophils; furthermore, TLR2, TLR4, and NLRP3 receptors were found to mediate the inducible effect of lipoprotein on the above inflammation mediators and cytokines, which depended on MAPK and Caspase-1 signaling pathways. In addition, TLR2, TLR4, and NLRP3 inhibitors significantly inhibited PGE2 and cytokine secretion, and PGE2 was involved in the interaction of S. aureus and neutrophils in dairy cows, which could be regulated by TLR2, TLR4, and NLRP3 receptors. We also found that S. aureus was more likely to be killed by neutrophils when it lacked lipoprotein and TLR2, TLR4, and NLRP3 were involved, but PGE2 seemed to have no effect.DiscussionTaken together, these results suggest that lipoprotein is a crucial component of S. aureus in inducing cytokine secretion by neutrophils as well as killing within neutrophils, which could be accomplished by the accumulation of PGE2 by activating MAPK and the Caspase-1 signaling pathways through TLR2, TLR4, and NLRP3 receptors. These results will contribute to a better understanding of the interaction between S. aureus and host immune cells in dairy cows.

Dataset Information

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

Publications

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

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