PMID- 30348171
OWN - NLM
STAT- MEDLINE
DCOM- 20181218
LR  - 20191210
IS  - 1742-2094 (Electronic)
IS  - 1742-2094 (Linking)
VI  - 15
IP  - 1
DP  - 2018 Oct 22
TI  - Innate immune activation of astrocytes impairs neurodevelopment via upregulation 
      of follistatin-like 1 and interferon-induced transmembrane protein 3.
PG  - 295
LID - 10.1186/s12974-018-1332-0 [doi]
LID - 295
AB  - BACKGROUND: Polyriboinosinic-polyribocytidylic acid (polyI:C) triggers a strong 
      innate immune response that mimics immune activation by viral infections. 
      Induction of interferon-induced transmembrane protein 3 (Ifitm3) in astrocytes 
      has a crucial role in polyI:C-induced neurodevelopmental abnormalities. Through a 
      quantitative proteomic screen, we previously identified candidate astroglial 
      factors, such as matrix metalloproteinase-3 (Mmp3) and follistatin-like 1 
      (Fstl1), in polyl:C-induced neurodevelopmental impairment. Here, we characterized 
      the Ifitm3-dependent inflammatory processes focusing on astrocyte-derived Fstl1 
      following polyI:C treatment to assess the neuropathologic role of Fstl1. METHODS: 
      Astrocytes were treated with PBS (control) or polyI:C (10 mug/mL). The conditioned 
      medium was collected 24 h after the polyI:C treatment and used as astrocyte 
      condition medium (ACM). The expression of Fstl1 mRNA and extracellular Fstl1 
      protein levels were analyzed by quantitative PCR and western blotting, 
      respectively. For functional studies, neurons were treated with ACM and the 
      effects of ACM on dendritic elongation were assayed. To examine the role of 
      Fstl1, recombinant Fstl1 protein and siRNA for Fstl1 were used. To investigate 
      the expression of Fstl1 in vivo, neonatal mice were treated with vehicle or 
      polyI:C on postnatal day 2 to 6. RESULTS: ACM prepared with polyI:C (polyI:C ACM) 
      contained significantly higher Fstl1 protein than control ACM, but no increase in 
      Fstl1 was observed in polyI:C ACM derived from Ifitm3-deficient astrocytes. We 
      found that the production of Fstl1 involves the inflammatory responsive molecule 
      Ifitm3 in astrocytes and influences neuronal differentiation. In agreement, the 
      levels of Fstl1 increased in the hippocampus of polyI:C-treated neonatal mice. 
      COS7 cells co-transfected with both Fstl1 and Ifitm3 had higher extracellular 
      levels of Fstl1 than the cells transfected with Fstl1 alone. Treatment of primary 
      cultured hippocampal neurons with recombinant Fstl1 impaired dendritic 
      elongation, and the deleterious effect of polyI:C ACM on dendritic elongation was 
      attenuated by knockdown of Fstl1 in astrocytes. CONCLUSIONS: The extracellular 
      level of Fstl1 is regulated by Ifitm3 in astrocytes, which could be involved in 
      polyI:C-induced neurodevelopmental impairment.
FAU - Yamada, Shinnosuke
AU  - Yamada S
AD  - Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University 
      Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, 
      Japan.
FAU - Itoh, Norimichi
AU  - Itoh N
AD  - Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University 
      Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, 
      Japan.
FAU - Nagai, Taku
AU  - Nagai T
AD  - Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University 
      Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, 
      Japan.
FAU - Nakai, Tsuyoshi
AU  - Nakai T
AD  - Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University 
      Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, 
      Japan.
FAU - Ibi, Daisuke
AU  - Ibi D
AD  - Department of Chemical Pharmacology, Faculty of Pharmaceutical Science, Meijo 
      University, 150 Yagotoyama, Tenpaku-ku, Nagoya, Japan.
FAU - Nakajima, Akira
AU  - Nakajima A
AD  - Faculty of Agriculture and Life Science, Hirosaki University, 3 Bunkyo-cho, 
      Hirosaki, Aomori, 036-8561, Japan.
FAU - Nabeshima, Toshitaka
AU  - Nabeshima T
AD  - Advanced Diagnostic System Research Laboratory, Fujita Health University, 
      Graduate School of Health Science and Aino University, 1-98 Dengakugakubo, 
      Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
FAU - Yamada, Kiyofumi
AU  - Yamada K
AD  - Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University 
      Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, 
      Japan. kyamada@med.nagoya-u.ac.jp.
LA  - eng
GR  - 17H04031/Grant-in Aid for Scientific Research (B)/
GR  - 17H04252/Grant-in Aid for Scientific Research (B)/
GR  - 17H02220/Grant-in Aid for Scientific Research (B)/
GR  - 16K15201/Grant-in Aid for Challenging Exploratory Research/
GR  - 17K19483/Grant-in Aid for Challenging Exploratory Research/
GR  - 24111518/Grant-in Aid for Scientific Research on Innovative Areas/
GR  - 16K21080/Grant-in Aid for Young Scientists (B)/
PT  - Journal Article
DEP - 20181022
PL  - England
TA  - J Neuroinflammation
JT  - Journal of neuroinflammation
JID - 101222974
RN  - 0 (CD11b Antigen)
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (Follistatin-Related Proteins)
RN  - 0 (Fstl1 protein, mouse)
RN  - 0 (Glial Fibrillary Acidic Protein)
RN  - 0 (Membrane Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (fragilis protein, mouse)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - O84C90HH2L (Poly I-C)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Astrocytes/chemistry/*drug effects
MH  - Brain/cytology
MH  - CD11b Antigen/metabolism
MH  - COS Cells
MH  - Cells, Cultured
MH  - Chlorocebus aethiops
MH  - Culture Media, Conditioned/chemistry/pharmacology
MH  - Dendrites/drug effects
MH  - Embryo, Mammalian
MH  - Follistatin-Related Proteins/genetics/*metabolism
MH  - Glial Fibrillary Acidic Protein/metabolism
MH  - Immunity, Innate/drug effects/*physiology
MH  - Matrix Metalloproteinase 3/metabolism
MH  - Membrane Proteins/genetics/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neurons/drug effects
MH  - Poly I-C/pharmacology
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Up-Regulation/drug effects/*physiology
PMC - PMC6198367
OTO - NOTNLM
OT  - Astrocyte
OT  - Fstl1
OT  - Ifitm3
OT  - Immune response
OT  - Neuron
OT  - Schizophrenia
OT  - Viral infection
OT  - polyI:C
COIS- ETHICS APPROVAL: This study was approved by the Institutional Animal Care and Use 
      Committee of Nagoya University (Approval No. 30248). Animals were handled in 
      accordance with the guidelines established by the Institutional Animal Care and 
      Use Committee of Nagoya University. CONSENT FOR PUBLICATION: Not applicable 
      COMPETING INTERESTS: The authors declare that they have no competing interests. 
      PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional 
      claims in published maps and institutional affiliations.
EDAT- 2018/10/24 06:00
MHDA- 2018/12/19 06:00
PMCR- 2018/10/22
CRDT- 2018/10/24 06:00
PHST- 2018/06/07 00:00 [received]
PHST- 2018/10/12 00:00 [accepted]
PHST- 2018/10/24 06:00 [entrez]
PHST- 2018/10/24 06:00 [pubmed]
PHST- 2018/12/19 06:00 [medline]
PHST- 2018/10/22 00:00 [pmc-release]
AID - 10.1186/s12974-018-1332-0 [pii]
AID - 1332 [pii]
AID - 10.1186/s12974-018-1332-0 [doi]
PST - epublish
SO  - J Neuroinflammation. 2018 Oct 22;15(1):295. doi: 10.1186/s12974-018-1332-0.