title: 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.affiliation: Department of Endocrinology, Metabolism, and Hypertension, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Endocrinology, Metabolism, and Hypertension, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan. Electronic address: masashi.7.tanaka@gmail.com.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Endocrinology, Metabolism, and Hypertension, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Masuda
authors.affiliation: Department of Endocrinology, Metabolism, and Hypertension, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ohue-Kitano
authors.affiliation: Department of Endocrinology, Metabolism, and Hypertension, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Yamakage
authors.affiliation: Department of Endocrinology, Metabolism, and Hypertension, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Muranaka
authors.affiliation: Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Wada
authors.affiliation: Department of Endocrinology, Metabolism, and Hypertension, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kusakabe
authors.affiliation: Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimatsu
authors.affiliation: Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Department of Endocrinology, Metabolism, and Hypertension, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Satoh-Asahara
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004281:Docosahexaenoic Acids / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005395:Fish Oils / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D054409:Nicotinamide Phosphoribosyltransferase / Q000096:biosynthesis; D012307:Risk Factors; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D015525:Fatty Acids, Omega-3; D005395:Fish Oils; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Autophagy; Inflammation; Microglia; NF-κB; SIRT1; ω-3 PUFAs