PGE2 inhibits neutrophil phagocytosis through the EP2R–cAMP–PTEN pathway

Abstract

Prostaglandin E2 (PGE2) is a potent lipid mediator of inflammation that modulates immune cell function by binding to unique G protein‐coupled receptors (EP receptors). PGE2 production increases during microbial infection and inflammation. In this study, we assessed the effect of PGE2 on the phagocytosis of bacteria by neutrophils, which are key players during infection and inflammation. We also looked for specific EP receptor signaling pathways that contributed to the neutrophil phagocytic activity. PGE2 (50–1000 ng/ml) inhibited the phagocytosis of Escherichia coli by HL‐60 human neutrophils in a concentration‐dependent manner. Inhibition of neutrophil phagocytosis by PGE2 correlated with increased intracellular cyclic adenosine monophosphate (cAMP) production, and forskolin, an adenosyl cyclase agonist, confirmed the inhibitory effect of cAMP stimulation on neutrophil phagocytosis. The expression of EP2 receptors by HL‐60 cells was confirmed by western blot analysis, and selective agonism of EP2 receptors mimicked the inhibition of phagocytosis by PGE2. The EP2 receptor antagonist AH‐6089 partially blocked the inhibition of neutrophil phagocytosis PGE2. Specific inhibition of phosphatase and tensin homolog (PTEN) enzyme attenuated the inhibition of neutrophil phagocytosis by PGE2, and both PGE2 and increased intracellular cAMP increased neutrophil PTEN activity, which was associated with decreased PTEN phosphorylation. The results support negative regulation of the antimicrobial activity of neutrophils (i.e., phagocytosis), which has important implications for the future management of bacterial infections.

Meloxicam treatment disrupts the regional structure of innate inflammation sites by targeting the pro‐inflammatory effects of prostanoids

“…Given that meloxicam treatment also inhibited phagocytosis by neutrophils and macrophages, the resulting slower clearance of pathogens would automatically prolong the inflammation. PGD 2 enhances the phagocytic activity of neutrophils and macrophages (Pereira et al, 2015(Pereira et al, , 2018, whereas PGE 2 is an inhibitor (Aronoff et al, 2004;Wang et al, 2022). Because phagocytic activity depends on the cell's interpretation of the sum of incoming positive and negative signals, the final regulation of phagocytosis by neutrophils and macrophages is likely to depend on additional input from other receptors and signalling pathways.…”

“…However, PGE 2 inhibits eosinophil migration whereas PGD 2 is a chemoattractant for eosinophils (Monneret et al, 2001;Sturm et al, 2008). Similarly, PGE 2 inhibits phagocytosis by neutrophils and macrophages (Aronoff et al, 2004;Wang et al, 2022) whereas PGD 2 suppresses phagocytic activity depending on the activated receptor subtype (Pereira et al, 2018).…”

“…However, PGE 2 inhibits eosinophil migration whereas PGD 2 is a chemoattractant for eosinophils (Monneret et al, 2001; Sturm et al, 2008). Similarly, PGE 2 inhibits phagocytosis by neutrophils and macrophages (Aronoff et al, 2004; Wang et al, 2022) whereas PGD 2 suppresses phagocytic activity depending on the activated receptor subtype (Pereira et al, 2018). Finally, PGE 2 polarizes macrophages towards M2‐like phenotypes (Schmid & Brüne, 2021) whereas PGD 2 and TXA 2 promote M1‐like polarization (Pereira et al, 2015; Pierre et al, 2017).…”

Treponema pallidum protein Tp47 induced prostaglandin E2 to inhibit the phagocytosis in human macrophages

“…Previous studies demonstrated that the production of PGE2 led to a reduction of phagocytosis in immune cells 24,25 . To assess the potential of Tp47 to promote PGE2 production by macrophages, cell supernatants were collected during the experiments in which macrophages were treated with different concentrations of Tp47 as described above.…”

“…Previous studies demonstrated that the production of PGE2 led to a reduction of phagocytosis in immune cells. 24,25 To assess the potential of Tp47 to promote PGE2 production by macrophages, cell supernatants were collected during the experiments in which macrophages were treated with different concentrations of Tp47 as described above. The results showed that the concentration of PGE2 produced by macrophages increased significantly with the increase of Tp47 concentration in a concentration-dependent manner (p < 0.001) (Figure 2a).…”