Small molecules inspired from endogenous vitamin E metabolites induce a lipid mediator class switch from inflammation to resolution in innate immune cells

Inflammation is a complex process driven by innate immune cells that produce pro-inflammatory lipid mediators during acute phase and specialized pro-resolving lipid mediators (SPM) in the resolution phase. Macrophages of the M2 subtype play a major role in inflammation resolution as they strongly express ALOX15 and ALOX15B and effectively release SPM, including resolvins, protectins and maresins. This lipid mediator class switch terminates inflammatory processes and restores tissue homeostasis. Current anti-inflammatory therapy largely targets pro-inflammatory cascades, without considering resolution. We have recently shown that endogenous metabolites of vitamin E cumulate in innate immune cells at inflammatory sites, limit inflammation by targeting 5-lipoxygenase (5-LOX) and raise systemic resolvin levels. Starting from an in-house library of 150 isolated and semi-synthesized vitamin derivatives, we searched for structurally optimized compounds that combine potent inhibition of 5-LOX with enhanced SPM biosynthesis. Lipid mediator profiles of activated and non-activated macrophages (M1 and M2), peripheral blood mononuclear cells and neutrophils were assessed. We identified specific ω-oxidized tocotrienol derivatives that selectively trigger the biosynthesis of protectins among SPM while maintaining the 5-LOX inhibitory activity. These lead compounds are of high interest as tools for studying protectin function and open the door to a novel class of anti-inflammatory/pro-resolving drug candidates that induce a switch from leukotrienes to protectins.

Publikationsverlauf

Artikel online veröffentlicht:
13. Dezember 2021