Omega-3 polyunsaturated fatty acids suppress the inflammatory responses of lipopolysaccharide-stimulated mouse microglia by activating SIRT1 pathways

Obesity and diabetes are known risk factors for dementia, and it is speculated that chronic neuroinflammation contributes to this increased risk. Microglia are brain-resident immune cells modulating the neuroinflammatory state. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major ω-...

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Published in:Biochimica et biophysica acta. Molecular and cell biology of lipids 2017-05, Vol.1862 (5), p.552-560
Main Authors: Inoue, Takayuki, Tanaka, Masashi, Masuda, Shinya, Ohue-Kitano, Ryuji, Yamakage, Hajime, Muranaka, Kazuya, Wada, Hiromichi, Kusakabe, Toru, Shimatsu, Akira, Hasegawa, Koji, Satoh-Asahara, Noriko
Format: Article
Language:English
Subjects:
Animals
Autophagy
Cytokines - biosynthesis
Docosahexaenoic Acids - metabolism
Eicosapentaenoic Acid - metabolism
Fatty Acids, Omega-3 - metabolism
Fish Oils - metabolism
Inflammation
Inflammation - chemically induced
Inflammation - genetics
Inflammation - metabolism
Inflammation - pathology
Lipopolysaccharides - toxicity
Mice
Microglia
Microglia - drug effects
Microglia - metabolism
Microglia - pathology
NF-κB
Nicotinamide Phosphoribosyltransferase - biosynthesis
Risk Factors
Signal Transduction
SIRT1
Sirtuin 1 - biosynthesis
Sirtuin 1 - genetics
Tumor Necrosis Factor-alpha - biosynthesis
ω-3 PUFAs
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Summary:Obesity and diabetes are known risk factors for dementia, and it is speculated that chronic neuroinflammation contributes to this increased risk. Microglia are brain-resident immune cells modulating the neuroinflammatory state. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major ω-3 polyunsaturated fatty acids (PUFAs) of fish oil, exhibit various effects, which include shifting microglia to the anti-inflammatory phenotype. To identify the molecular mechanisms involved, we examined the impact of EPA, DHA, and EPA+DHA on the lipopolysaccharide (LPS)-induced cytokine profiles and the associated signaling pathways in the mouse microglial line MG6. Both EPA and DHA suppressed the production of the pro-inflammatory cytokines TNF-α and IL-6 by LPS-stimulated MG6 cells, and this was also observed in LPS-stimulated BV-2 cells, the other microglial line. Moreover, the EPA+DHA mixture activated SIRT1 signaling by enhancing mRNA level of nicotinamide phosphoribosyltransferase (NAMPT), cellular NAD+ level, SIRT1 protein deacetylase activity, and SIRT1 mRNA levels in LPS-stimulated MG6. EPA+DHA also inhibited phosphorylation of the stress-associated transcription factor NF-κB subunit p65 at Ser536, which is known to enhance NF-κB nuclear translocation and transcriptional activity, including cytokine gene activation. Further, EPA+DHA increased the LC3-II/LC3-I ratio, an indicator of autophagy. Suppression of TNF-α and IL-6 production, inhibition of p65 phosphorylation, and autophagy induction were abrogated by a SIRT1 inhibitor. On the other hand, NAMPT inhibition reversed TNF-α suppression but not IL-6 suppression. Accordingly, these ω-3 PUFAs may suppress neuroinflammation through SIRT1-mediated inhibition of the microglial NF-κB stress response and ensue pro-inflammatory cytokine release, which is implicated in NAMPT-related and –unrelated pathways. •ω-3 PUFAs exhibit anti-inflammatory effects on LPS-stimulated microglia.•ω-3 PUFAs inhibit NF-kB signaling through activation of SIRT1-mediated pathway.•ω-3 PUFAs induce the indicative of autophagy induction via SIRT1-mediated pathway.
ISSN:1388-1981
1879-2618
1879-2618
DOI:10.1016/j.bbalip.2017.02.010