PGE2 Augments Inflammasome Activation and M1 Polarization in Macrophages Infected With Salmonella Typhimurium and Yersinia enterocolitica

Abstract

Eicosanoids are cellular metabolites, which shape the immune response, including inflammatory processes in macrophages. The effects of these lipid mediators on inflammation and bacterial pathogenesis are not clearly understood. Certain eicosanoids are suspected to act as molecular sensors for the recruitment of neutrophils, while others regulate bacterial uptake. In this study, gene expression analyses indicated that genes involved in eicosanoid biosynthesis including COX-1, COX-2, DAGL, and PLA-2 are differentially regulated in THP-1 human macrophages infected with Salmonella enterica Typhimurium or Yersinia enterocolitica. By using targeted metabolomics approach, we found that the eicosanoid precursor, arachidonic acid (AA) as well as its derivatives, including prostaglandins (PGs) PGF2α or PGE2/PGD2, and thromboxane TxB2, are rapidly secreted from macrophages infected with these Gram-negative pathogenic bacteria. The magnitude of eicosanoid biosynthesis in infected host cells depends on the presence of virulence factors of Y. enterocolitica and S. Typhimurium strains, albeit in an opposite way in Y. enterocolitica compared to S. Typhimurium infection. Trials with combinations of EP2/EP4 PGE2 receptor agonists and antagonists suggest that PGE2 signaling in these infection models works primarily through the EP4 receptor. Downstream of EP4 activation, PGE2 enhances inflammasome activation and represses M2 macrophage polarization while inducing key M1-type markers. PGE2 also led to a decreased numbers of Y. enterocolitica within macrophages. To summarize, PGE2 is a potent autocrine/paracrine activator of inflammation during infection in Gram-negative bacteria, and it affects macrophage polarization, likely controlling bacterial clearance by macrophages.

Non‐steroidal anti‐inflammatory drugs, prostaglandins, and COVID‐19

“…(Mortimer, Moreau, Mac-Donald, & Chadee, 2016;Sokolowska et al, 2015). However, other authors report positive effects of PGE 2 upon NLRP3 inflammasome activation and IL-1β production in macrophages and monocytes under various stimuli (Nakata et al, 2020;Sheppe et al, 2018;Zasłona et al, 2017). Taken together, these findings indicate contextdependent modulation of NLRP3 inflammasome activation by PGE 2 .…”

Evaluation of Glycosylated PTGS2 in Colorectal Cancer for NSAIDS-Based Adjuvant Therapy

“…In Apc (Min/+) mice, the inhibition of PTGS2 reduces the M2 component [19]; thus, the expression of PTGS2 in CRC macrophages could be associated to the induction of a prevalent M2 phenotype. On the other hand, PGE2 is able to induce M1 differentiation in other mouse models [20], suggesting a positive influence of PTGS2 on the M1 component. We first tested the correspondence of PTGS2 expression with CD68 and CD163 on serial sections, assuming that CD68 positivity would indicate the total macrophage population, while CD163 would indicate the M2 component.…”

Opposing effects of IL-1β/COX-2/PGE2 pathway loop on islets in type 2 diabetes mellitus

“…It is well known that COX-2 plays a key role in PGE2 biosynthesis, which is related to proinflammatory reactions [12][13][14]. To determine the function of COX-2 in β cells, we first examined the effect of PGE2, the classical product of COX-2, on the β cell function.…”