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.
Highlights
We hypothesized that the expression of specific genes regulating eicosanoid biosynthesis in human macrophages is modulated at early stages of S
diacylglycerol lipase (DAGL) is an essential component of the endocannabinoid system, hydrolyzing diacylglycerol to 2-arachidonoylglycerol (2-AG), where 2-AG can serve as an alternative pathway to obtain prostaglandin precursors
arachidonic acid (AA) is a substrate for COX-1 and COX-2 enzymes, which catalyze the oxygenation of this polyunsaturated fatty acid into endoperoxide prostaglandin H2 (PGH2)
Summary
Typhimurium infection, but many details remain unanswered, such as how host metabolites activate the innate immune responses for bacterial clearance. A metabolic profiling study in animal tissue identified upregulation of the PGD2 metabolite 15-deoxy- 12,14-PGJ2 upon Salmonella infection (Antunes et al, 2011). This eicosanoid was shown to successfully prevent bacterial colonization during Salmonella infection of mouse and human macrophages (Buckner et al, 2013). The function of eicosanoids such as PGE2 in inflammasome activation remains controversial, and their role in the clearance of Gram-negative infections by phagocytic cells remains vastly unknown. Typhimurium infection leads to an inflammasome activation in infected macrophages, which is controlled by Salmonella Pathogenicity 1 and 2 (SPI-1 and SPI-2) effectors
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