Docosahexaenoyl serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate has anti-inflammatory properties by attenuating IL-23-IL-17 signaling in macrophages.
Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signaling molecules. Among these, the ethanolamine conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties. Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signaling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4+ Th17 response. Hence, levels of PGE2, IL-6, IL-1β, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100-500nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease (IBD) and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signaling pathway in the etiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. IBD or intestinal tumorigenesis.
Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands. Electronic address: mieke.poland@wur.nl.
Mieke
M
Poland
Institute for Life Sciences & Chemistry, Utrecht University of Applied Sciences, Utrecht, The Netherlands. Electronic address: jeanpaul.tenklooster@hu.nl.
Jean Paul
JP
Ten Klooster
Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands. Electronic address: wz8918@163.com.
Zheng
Z
Wang
Institute for Life Sciences & Chemistry, Utrecht University of Applied Sciences, Utrecht, The Netherlands. Electronic address: raymond.pieters@hu.nl.
Raymond
R
Pieters
Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands. Electronic address: mark.boekschoten@wur.nl.
Mark
M
Boekschoten
Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands. Electronic address: renger.witkamp@wur.nl.
Renger
R
Witkamp
Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands. Electronic address: jocelijn.meijerink@wur.nl.
Jocelijn
J
Meijerink
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D018836:Inflammation Mediators / Q000494:pharmacology; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D000067996:RAW 264.7 Cells; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058504:Th17 Cells / Q000187:drug effects / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D015525:Fatty Acids, Omega-3; D018836:Inflammation Mediators; D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D015850:Interleukin-6; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D004281:Docosahexaenoic Acids; D012701:Serotonin; D015118:Eicosapentaenoic Acid
Acyl serotonines; DHA; DHA-5-HT; Endocannabinoids; Intestine; Nrf2