Human macrophages differentially produce specific resolvin or leukotriene signals that depend on bacterial pathogenicity

Abstract

Proinflammatory eicosanoids (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPM) are temporally regulated during infections. Here we show that human macrophage phenotypes biosynthesize unique lipid mediator signatures when exposed to pathogenic bacteria. E. coli and S. aureus each stimulate predominantly proinflammatory 5-lipoxygenase (LOX) and cyclooxygenase pathways (i.e., leukotriene B4 and prostaglandin E2) in M1 macrophages. These pathogens stimulate M2 macrophages to produce SPMs including resolvin D2 (RvD2), RvD5, and maresin-1. E. coli activates M2 macrophages to translocate 5-LOX and 15-LOX-1 to different subcellular locales in a Ca2+-dependent manner. Neither attenuated nor non-pathogenic E. coli mobilize Ca2+ or activate LOXs, rather these bacteria stimulate prostaglandin production. RvD5 is more potent than leukotriene B4 at enhancing macrophage phagocytosis. These results indicate that M1 and M2 macrophages respond to pathogenic bacteria differently, producing either leukotrienes or resolvins that further distinguish inflammatory or pro-resolving phenotypes.

Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome

“…The sample size for experiments was chosen empirically based on previous studies (12,20) to ensure adequate statistical power.…”

“…Expression of 15‐LOX‐1 is characteristic for the M2 phenotype, as well as its high capacity to biosynthesize SPM compared with the M1 subset (12). However, 15‐LOX‐1 is a versatile enzyme that plays a role in both the onset and the termination of immune responses (10, 11, 57, 58).…”

Leukocytes from obese individuals exhibit an impaired SPM signature

“…In addition to this, our data demonstrated that 5-LOX protein levels and phosphorylation of Ser271 of 5-LOX were significantly reduced in leukocytes from obese individuals. Because Ser271 phosphorylation has been shown to inhibit the nuclear export of 5-LOX (29), these findings suggest that in obese leukocytes, 5-LOX would be mostly localized in the nucleus instead of the cytoplasm, which is a trait that would favor and not hamper the biosynthesis of SPMs by these cells (30)(31)(32)(33). However, confocal microscopy analyses could not confirm this counterintuitive finding and only proved a less intense 5-LOX signal and a distinct intracellular redistribution of this enzyme in leukocytes from obese individuals.…”

Pro-Resolving Mediator Profiles And 5-Lipoxygenase Activity In Cerebrospinal Fluid Correlate with Disease Severity and Outcome in Adults with Tuberculous Meningitis

“…Leukocytes play an important role in the biosynthesis of lipid mediators, with their product profile reflecting their activation status (23–25). Different macrophage subsets, for example, display distinct lipid mediator profiles with monocyte-derived-macrophages skewed towards a classic phenotype expressing higher amounts of pro-inflammatory eicosanoids, whereas cells with an alternatively activated phenotype display higher concentrations of pro-resolving mediators (23–25). This shift is also linked with a differential expression of both lipid mediator biosynthetic enzymes as well as the phosphorylation status of ALOX5 (23, 25, 26).…”