title: 15-Lipoxygenase metabolites of α-linolenic acid, [13-(S)-HPOTrE and 13-(S)-HOTrE], mediate anti-inflammatory effects by inactivating NLRP3 inflammasome.
abstract: The ratio of ω-6 to ω-3 polyunsaturated fatty acids (PUFAs) appears to be critical in the regulation of various pathophysiological processes and to maintain cellular homeostasis. While a high proportion of dietary intake of ω-6 PUFAs is associated with various inflammatory disorders, higher intake of ω-3 PUFAs is known to offer protection. It is now well established that beneficial effects of ω-3 PUFAs are mediated in part by their oxygenated metabolites mainly via the lipoxygenase (LOX) and cyclooxygenase (COX) pathways. However, the down-stream signaling pathways that are involved in these anti-inflammatory effects of ω-3 PUFAs have not been elucidated. The present study evaluates the effects of 15-LOX metabolites of α-linolenic acid (ALA, ω-3 PUFA) on lipopolysaccharide (LPS) induced inflammation in RAW 264.7 cells and peritoneal macrophages. Further, the effect of these metabolites on the survival of BALB/c mice in LPS mediated septic shock and also polymicrobial sepsis in Cecal Ligation and Puncture (CLP) mouse model was studied. These studies reveal the anti-inflammatory effects of 13-(S)-hydroperoxyoctadecatrienoic acid [13-(S)-HPOTrE] and 13-(S)-hydroxyoctadecatrienoic acid [13-(S)-HOTrE] by inactivating NLRP3 inflammasome complex through the PPAR-γ pathway. Additionally, both metabolites also deactivated autophagy and induced apoptosis. In mediating all these effects 13-(S)-HPOTrE was more potent than 13-(S)-HOTrE.
authors.affiliation: School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.affiliation: School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
authors.forename: Geetika
authors.initials: G
authors.lastname: Gupta
authors.affiliation: National Institute of Animal Biotechnology, Hyderabad 500049, India.
authors.forename: Kotha
authors.initials: K
authors.lastname: Anilkumar
authors.affiliation: School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
authors.forename: Naireen
authors.initials: N
authors.lastname: Fatima
authors.affiliation: School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
authors.forename: Roy
authors.initials: R
authors.lastname: Karnati
authors.affiliation: School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
authors.forename: Gorla Venkateswara
authors.initials: GV
authors.lastname: Reddy
authors.affiliation: School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
authors.forename: Priyanka Voori
authors.initials: PV
authors.lastname: Giri
authors.affiliation: School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
authors.forename: Pallu
authors.initials: P
authors.lastname: Reddanna
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D017962:alpha-Linolenic Acid / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D058847:Inflammasomes; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017962:alpha-Linolenic Acid; D001093:Arachidonate 15-Lipoxygenase