Role of Suppressor of Cytokine Signaling 3 (SOCS3) in Altering Activated Microglia Phenotype in APPswe/PS1dE9 Mice.
In response to changes of the central nervous system environment, microglia are capable of acquiring diverse phenotypes for cytotoxic or immune regulation and resolution of injury. Alzheimer's disease (AD) pathology also induces several microglial activations, resulting in production of pro-inflammatory cytokines and reactive oxygen species or clearance of amyloid-β (Aβ) through phagocytosis. We previously demonstrated that microglial activation and increase in oxidative stress started from the middle age in APPswe/PS1dE9 mice, and hypothesized that M1 activation occurs in middle-aged AD mice by Aβ stimulation. In the present study, we analyzed in vivo expressions of pro-inflammatory cytokines (M1 microglial markers), M2 microglial markers, and suppressor of cytokine signaling (SOCS) family, and examined the microglial phenotypic profile in APPswe/PS1dE9 mice. Then we compared the in vitro gene expression patterns of Aβ- and lipopolysaccharide (LPS)-stimulated primary-cultured microglia. Microglia in APPswe/PS1dE9 mice exhibited an M1-like phenotype, expressing tumor necrosis factor α (TNFα) but not interleukin 6 (IL6). Aβ-stimulated primary-cultured microglia also expressed TNFα but not IL6, whereas LPS-stimulated primary-cultured microglia expressed both pro-inflammatory cytokines. Furthermore, both microglia in APPswe/PS1dE9 mice and Aβ-stimulated primary-cultured microglia expressed SOCS3. Reduction of SOCS3 expression in Aβ-challenged primary-cultured microglia resulted in upregulation of IL6 expression. Our findings indicate that SOCS3 suppresses complete polarization to M1 phenotype through blocking IL6 production, and Aβ-challenged primary-cultured microglia replicate the in vivo gene expression pattern of microglia in APPswe/PS1dE9 mice. Aβ may induce the M1-like phenotype through blocking of IL6 by SOCS3.
Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
Naotoshi
N
Iwahara
Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
Shin
S
Hisahara
Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
Jun
J
Kawamata
Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
Akihiro
A
Matsumura
Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
Kazuki
K
Yokokawa
Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
Taro
T
Saito
Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
Mai
M
Fujikura
Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
Tatsuo
T
Manabe
Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
Hiromi
H
Suzuki
Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.|Department of Pharmacology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
Takashi
T
Matsushita
Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
Syuuichirou
S
Suzuki
Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.
Shun
S
Shimohama
D000544:Alzheimer Disease / Q000276:immunology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000276:immunology / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015850:Interleukin-6; D008070:Lipopolysaccharides; C508853:PSEN1 protein, human; D053764:Presenilin-1; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse
APPswe/PS1dE9 mice; Alzheimer’s disease; IL6; SOCS3; STAT3; amyloid-β; inflammation; microglia