title: Dual role of superoxide dismutase 2 induced in activated microglia: oxidative stress tolerance and convergence of inflammatory responses.
abstract: Microglia are activated quickly in response to external pathogens or cell debris and clear these substances via the inflammatory response. However, excessive activation of microglia can be harmful to host cells due to the increased production of reactive oxygen species and proinflammatory cytokines. Superoxide dismutase 2 (SOD2) is reportedly induced under various inflammatory conditions in the central nervous system. We herein demonstrated that activated microglia strongly express SOD2 and examined the role of SOD2, focusing on regulation of the microglial activity and the susceptibility of microglia to oxidative stress. When rat primary microglia were treated with LPS, poly(I:C), peptidoglycan, or CpG oligodeoxynucleotide, respectively, the mRNA and protein levels of SOD2 largely increased. However, an increased expression of SOD2 was not detected in the primary neurons or astrocytes, indicating that SOD2 is specifically induced in microglia under inflammatory conditions. The activated microglia showed high tolerance to oxidative stress, whereas SOD2 knockdown conferred vulnerability to oxidative stress. Interestingly, the production of proinflammatory cytokines was increased in the activated microglia treated with SOD2 siRNA compared with that observed in the control siRNA-treated cells. Pretreatment with NADPH oxidase inhibitors, diphenylene iodonium and apocynin, decreased in not only reactive oxygen species generation but also the proinflammatory cytokine expression. Notably, SOD2 knockdown largely potentiated the nuclear factor κB activity in the activated microglia. Taken together, increased SOD2 conferred tolerance to oxidative stress in the microglia and decreased proinflammatory cytokine production by attenuating the nuclear factor κB activity. Therefore, SOD2 might regulate neuroinflammation by controlling the microglial activities.
authors.affiliation: From the Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan and ishiyasu@hiroshima-u.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishihara
authors.affiliation: From the Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan and.
authors.forename: Takuya
authors.initials: T
authors.lastname: Takemoto
authors.affiliation: the Laboratory for Brain Science, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa, 769-2193, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Itoh
authors.affiliation: From the Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan and.
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Ishida
authors.affiliation: From the Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan and.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamazaki
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000201:enzymology* / Q000473:pathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D018384:Oxidative Stress; D011070:Poly I-C / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D000099156:Superoxide Dismutase 2
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D019255:NADPH Oxidases; D009838:Oligodeoxyribonucleotides; D011070:Poly I-C; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C408982:CPG-oligonucleotide
keywords: NF-kappaB; inflammation; microglia; oxidative stress; superoxide dismutase (SOD)