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

Abstract

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.

• Authors: Takayuki Inoue, Masashi Tanaka, Shinya Masuda, Ryuji Ohue-Kitano, Hajime Yamakage, Kazuya Muranaka, Hiromichi Wada, Toru Kusakabe, Akira Shimatsu, Koji Hasegawa, Noriko Satoh-Asahara
• Journal: Biochimica et biophysica acta. Molecular and cell biology of lipids (Biochim Biophys Acta Mol Cell Biol Lipids) Vol. 1862 Issue 5 Pg. 552-560 (May 2017) ISSN: 1388-1981 [Print] Netherlands
• PMID: 28254441 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Cytokines
• Fatty Acids, Omega-3
• Fish Oils
• Lipopolysaccharides
• Tumor Necrosis Factor-alpha
• Docosahexaenoic Acids
• Eicosapentaenoic Acid
• Nicotinamide Phosphoribosyltransferase
• nicotinamide phosphoribosyltransferase, mouse
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• Animals
• Cytokines (biosynthesis)
• Docosahexaenoic Acids (metabolism)
• Eicosapentaenoic Acid (metabolism)
• Fatty Acids, Omega-3 (metabolism)
• Fish Oils (metabolism)
• Inflammation (chemically induced, genetics, metabolism, pathology)
• Lipopolysaccharides (toxicity)
• Mice
• Microglia (drug effects, metabolism, pathology)
• Nicotinamide Phosphoribosyltransferase (biosynthesis)
• Risk Factors
• Signal Transduction
• Sirtuin 1 (biosynthesis, genetics)
• Tumor Necrosis Factor-alpha (biosynthesis)