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 Gramnegative bacteria, and it affects macrophage polarization, likely controlling bacterial clearance by macrophages.

Lipid droplet accumulation occurs early following Salmonella infection and contributes to intracellular bacterial survival and replication

“…Our next step was to investigate whether LD biogenesis could be influencing the release of interleukin‐1β (IL‐1β) (Figure 4h), interleukin‐6 (IL‐6) (Figure 4i), and C‐C Motif Chemokine Ligand 2 (CCL2) (Figure 4j) after 24 hpi, well‐known inflammatory mediators induced by Salmonella infection (Diamond et al., 2017; Hui et al., 2018; Sheppe et al., 2018; Weinstein et al., 1997). In this model, no correlation between LD accumulation and the level of the analyzed cytokines was observed (Figure 4h,j).…”

“…In general, the participation of LDs as a site of PGE 2 synthesis has been associated with an anti‐inflammatory phenotype in macrophages, favoring the inhibition of killing activity, the downregulation of Th1‐type cytokines, and raising the IL‐10 generation (Almeida et al., 2009; D’Avila et al., 2008; Mattos, Lara, et al., 2011). However, the PGE 2 appears to have a different effect in Salmonella ‐infected macrophages, inducing a specific pro‐inflammatory profile and amplifying the pro‐inflammatory response but decreasing macrophages’ antimicrobial activity (Sheppe et al., 2018). Moreover, intestinal pro‐inflammatory monocytes were an important niche to Salmonella proliferation (McLaughlin et al., 2019).…”