Stereochemical assignment and anti-inflammatory properties of the omega-3 lipid mediator resolvin E3

Abstract

Uncontrolled inflammation is now considered to be a link between many widely occurring diseases. Thus, controlling the innate inflammatory response and its local chemical mediators has been receiving increasing attention. We recently identified a novel family of eicosapentaenoic acid (EPA)-derived mediators produced by eosinophils, denoted as resolvin E3 (RvE3), that possess potent anti-inflammatory actions both in vitro and in vivo. Carbons at 17 and 18 positions are asymmetric and thus the molecule has a total of four potential stereoisomers. Here, we assigned the stereochemistry of the conjugated double bonds and chirality of alcohols present in two natural isomers of RvE3 with four different stereoisomers prepared by total organic synthesis. The complete structures of two natural isomers of RvE3 were determined to be 17R,18S- and 17R,18R-dihydroxy-5Z,8Z,11Z,13E,15E-EPA, respectively. These natural isomers prepared by total organic synthesis displayed a potent anti-inflammatory action by limiting neutrophil infiltrations both in vitro and in vivo. The unnatural stereoisomers were much less active compared with the natural isomers, demonstrating the stereoselective action of RvE3.

Pro-resolving lipid mediators are leads for resolution physiology

“…LC-MS-MS-lipidomics identified LXA 4 , RvD5, 17-HDHA and PD1 from eosinophils and RvE3 in vivo (Fig. 2) that limit PMN infiltration and regulate MΦ 44–46 . Hence, via their ability to produce SPM, eosinophils may contribute to resolution.…”

The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution

“…LC-MS-MS-lipidomics identified LXA 4 , RvD5, 17-HDHA and PD1 eosinophil production [51] and RvE3 (Fig. 2) that limit PMN infiltration and regulate MΦ [50, 52]. Hence, via their ability to produce SPM, eosinophils contribute to resolution.…”

Resolution of Acute Inflammation in the Lung

“…The third member of the E-series resolvins is resolvin E3 (17R,18S-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaenoic acid). There is also a natural 18R stereoisomer of RvE3 (85). As demonstrated in mice, this molecule is generated via the actions of 12/15-LOX so has a distinct route of biosynthesis from RvE1 and RvE2 (86).…”