15-Lipoxygenase metabolites of [alpha]-linolenic acid, [13-(S)-HPOTrE and 13-(S)-HOTrE], mediate anti-inflammatory effects by inactivating NLRP3 inflammasome

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 o...

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Published in:Scientific reports 2016-08, Vol.6, p.31649
Main Authors: Kumar, Naresh, Gupta, Geetika, Anilkumar, Kotha, Fatima, Naireen, Karnati, Roy, Reddy, Gorla Venkateswara, Giri, Priyanka Voori, Reddanna, Pallu
Format: Article
Language:English
Subjects:
Apoptosis
Cecum
Dietary intake
Homeostasis
Inflammasomes
Inflammatory diseases
Linolenic acid
Lipopolysaccharides
Lipoxygenase
Macrophages
Metabolites
Peritoneum
Peroxisome proliferator-activated receptors
Phagocytosis
Polyunsaturated fatty acids
Prostaglandin endoperoxide synthase
Rodents
Sepsis
Septic shock
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Summary: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.
ISSN:2045-2322
DOI:10.1038/srep31649