Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase

• Published in: Nature communications Vol. 9; no. 1; pp. 3834 - 17
• Main Authors: Pein, Helmut, Ville, Alexia, Pace, Simona, Temml, Veronika, Garscha, Ulrike, Raasch, Martin, Alsabil, Khaled, Viault, Guillaume, Dinh, Chau-Phi, Guilet, David, Troisi, Fabiana, Neukirch, Konstantin, König, Stefanie, Bilancia, Rosella, Waltenberger, Birgit, Stuppner, Hermann, Wallert, Maria, Lorkowski, Stefan, Weinigel, Christina, Rummler, Silke, Birringer, Marc, Roviezzo, Fiorentina, Sautebin, Lidia, Helesbeux, Jean-Jacques, Séraphin, Denis, Mosig, Alexander S., Schuster, Daniela, Rossi, Antonietta, Richomme, Pascal, Werz, Oliver, Koeberle, Andreas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20-09-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 101/62; 13; 13/95; 14; 38/70; 631/250/24/2510; 631/250/2504/223; 631/45/287; 639/638/309/436; 64/60; 82/16; 96/98; Adolescent; Adult; Aged; Allosteric properties; Animal models; Animals; Arachidonate 5-lipoxygenase; Arachidonate 5-Lipoxygenase - chemistry; Arachidonate 5-Lipoxygenase - metabolism; Asthma; Bioaccumulation; Biosynthesis; Bronchial Hyperreactivity - pathology; Carboxylates; Cell Survival - drug effects; Cell-Free System; Exudates; Exudation; Humanities and Social Sciences; Humans; Immune system; Inflammation; Inflammation - pathology; Inhibitory Concentration 50; Leukocytes; Leukocytes - metabolism; Leukotrienes; Life Sciences; Lipoxygenase; Lipoxygenase Inhibitors - pharmacology; Liver; Liver - drug effects; Liver - metabolism; Metabolites; Metabolome; Mice; Middle Aged; multidisciplinary; Peritonitis; Peritonitis - pathology; Recombinant Proteins - metabolism; Science; Science (multidisciplinary); Tocopherol; Vasoactive agents; Vitamin E; Vitamin E - chemistry; Vitamin E - metabolism; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06158-5

Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2
R
)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13′-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8–49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13′-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13′-COOH, potentially through inhibiting 5-lipoxygenase in immune cells.
Vitamin E metabolites are proposed to have signalling capacity, but how they may regulate immune responses is still unclear. Here the authors show that a vitamin E metabolite, α-T-13′-COOH, can inhibit 5-lipoxygenase and thereby suppress the synthesis of lipid mediators of immune activation and inflammatory responses.