Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation
Sungwhan F. Oh, … , Rong Yang, Charles N. Serhan
Sungwhan F. Oh, … , Rong Yang, Charles N. Serhan
Published January 4, 2011
Citation Information: J Clin Invest. 2011;121(2):569-581. https://doi.org/10.1172/JCI42545.
View: Text | PDF
Research Article Immunology

Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation

Abstract

E-series resolvins are antiinflammatory and pro-resolving lipid mediators derived from the ω-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) that actively clear inflammation to promote tissue homeostasis. Aspirin, in addition to exerting antithrombotic actions, also triggers the biosynthesis of these specialized pro-resolving mediators. Here, we used metabolomic profiling to investigate the biosynthesis of E-series resolvins with specific chiral chemistry in serum from human subjects and present evidence for new 18S series resolvins. Aspirin increased endogenous formation of 18S-hydroxyeicosapentaenoate (18S-HEPE) compared with 18R-HEPE, a known resolvin precursor. Human recombinant 5-lipoxygenase used both enantiomers as substrates, and recombinant LTA4 hydrolase (LTA4H) converted chiral 5S(6)-epoxide–containing intermediates to resolvin E1 and 18S-resolvin E1 (RvE1 and 18S-RvE1, respectively). 18S-RvE1 bound to the leukocyte GPCRs ChemR23 and BLT1 with increased affinity and potency compared with the R-epimer, but was more rapidly inactivated than RvE1 by dehydrogenase. Like RvE1, 18S-RvE1 enhanced macrophage phagocytosis of zymosan, E. coli, and apoptotic neutrophils and reduced both neutrophil infiltration and proinflammatory cytokines in murine peritonitis. These results demonstrate two parallel stereospecific pathways in the biosynthesis of E-series resolvins, 18R- and 18S-, which are antiinflammatory, pro-resolving, and non-phlogistic and may contribute to the beneficial actions of aspirin and ω-3 polyunsaturated fatty acids.

Authors

Sungwhan F. Oh, Padmini S. Pillai, Antonio Recchiuti, Rong Yang, Charles N. Serhan

×

Figure 9

Transient bioactions of 18S-RvE1.

Options: View larger image (or click on image) Download as PowerPoint
Transient bioactions of 18S-RvE1. (A) Regulation of PMN infiltration...
(A) Regulation of PMN infiltration during E. coli peritonitis by 18S-RvE1 and RvE1. 18S-RvE1 or RvE1 (100 ng) was administered via tail vein 3 hours after E. coli injection to peritoneum. **P < 0.01 compared with vehicle-treated. (B) Enhancement of neutrophil removal from site of inflammation: Vehicle, 100 ng RvE1, or 18S-RvE1 was injected intraperitoneally at 8 hours after zymosan A injection, and PMNs in the peritoneum were enumerated 12 hours later (20 hours after zymosan injection). Each point is the average from 3 mice with the same treatment on the same day. Results in A and B are mean ± SEM. †P < 0.05, 18S-RvE1 versus RvE1; *P < 0.05 compared with vehicle-treated. (C) Regulation of zymosan-stimulated mouse macrophage cytokine production by RvE1 and 18S-RvE1. Cell supernatants were collected and centrifuged for multiplex cytokine quantitation. Results are averages of duplicated measurements; *P < 0.05, **P < 0.01 compared with cells exposed to zymosan alone.