PMID- 31231866
OWN - NLM
STAT- MEDLINE
DCOM- 20200316
LR  - 20200316
IS  - 1098-1136 (Electronic)
IS  - 0894-1491 (Linking)
VI  - 67
IP  - 10
DP  - 2019 Oct
TI  - Neural sphingosine 1-phosphate accumulation activates microglia and links 
      impaired autophagy and inflammation.
PG  - 1859-1872
LID - 10.1002/glia.23663 [doi]
AB  - Microglia mediated responses to neuronal damage in the form of neuroinflammation 
      is a common thread propagating neuropathology. In this study, we investigated the 
      microglial alterations occurring as a result of sphingosine 1-phosphate (S1P) 
      accumulation in neural cells. We evidenced increased microglial activation in the 
      brains of neural S1P-lyase (SGPL1) ablated mice (SGPL1(fl/fl/Nes) ) as shown by 
      an activated and deramified morphology and increased activation markers on 
      microglia. In addition, an increase of pro-inflammatory cytokines in sorted and 
      primary cultured microglia generated from SGPL1 deficient mice was noticed. 
      Further, we assessed autophagy, one of the major mechanisms in the brain that 
      keeps inflammation in check. Indeed, microglial inflammation was accompanied by 
      defective microglial autophagy in SGPL1 ablated mice. Rescuing autophagy by 
      treatment with rapamycin was sufficient to decrease interleukin 6 (IL-6) but not 
      tumor necrosis factor (TNF) secretion in cultured microglia. Rapamycin mediated 
      decrease of IL-6 secretion suggests a particular mechanistic target of rapamycin 
      (mTOR)-IL-6 link and appeared to be microglia specific. Using pharmacological 
      inhibitors of the major receptors of S1P expressed in the microglia, we 
      identified S1P receptor 2 (S1PR2) as the mediator of both impaired autophagy and 
      proinflammatory effects. In line with these results, the addition of exogenous 
      S1P to BV2 microglial cells showed similar effects as those observed in the 
      genetic knock out of SGPL1 in the neural cells. In summary, we show a novel role 
      of the S1P-S1PR2 axis in the microglia of mice with neural-targeted SGPL1 
      ablation and in BV2 microglial cell line exogenously treated with S1P.
CI  - (c) 2019 Wiley Periodicals, Inc.
FAU - Karunakaran, Indulekha
AU  - Karunakaran I
AD  - LIMES Institute, Membrane Biology & Lipid Biochemistry, University of Bonn, 
      Germany.
AD  - Institute for Medical Microbiology, Immunology and Parasitology, University 
      Hospital of Bonn, Bonn, Germany.
FAU - Alam, Shah
AU  - Alam S
AD  - LIMES Institute, Membrane Biology & Lipid Biochemistry, University of Bonn, 
      Germany.
FAU - Jayagopi, Surendar
AU  - Jayagopi S
AD  - Institute for Medical Microbiology, Immunology and Parasitology, University 
      Hospital of Bonn, Bonn, Germany.
FAU - Frohberger, Stefan J
AU  - Frohberger SJ
AD  - Institute for Medical Microbiology, Immunology and Parasitology, University 
      Hospital of Bonn, Bonn, Germany.
FAU - Hansen, Jan N
AU  - Hansen JN
AUID- ORCID: 0000-0002-0489-7535
AD  - German Center for Neurodegenerative Diseases, DZNE, Bonn, Germany and Center of 
      Advanced European Studies and Research, Bonn, Germany.
FAU - Kuehlwein, Janina
AU  - Kuehlwein J
AD  - Institute for Medical Microbiology, Immunology and Parasitology, University 
      Hospital of Bonn, Bonn, Germany.
FAU - Holbling, Benedikt V
AU  - Holbling BV
AD  - German Center for Neurodegenerative Diseases, DZNE, Bonn, Germany and Center of 
      Advanced European Studies and Research, Bonn, Germany.
FAU - Schumak, Beatrix
AU  - Schumak B
AD  - Institute for Medical Microbiology, Immunology and Parasitology, University 
      Hospital of Bonn, Bonn, Germany.
FAU - Hubner, Marc P
AU  - Hubner MP
AD  - Institute for Medical Microbiology, Immunology and Parasitology, University 
      Hospital of Bonn, Bonn, Germany.
FAU - Graler, Markus H
AU  - Graler MH
AD  - Department of Anaesthesiology and Intensive Care Medicine, Center for Sepsis 
      Control and Care (CSCC), and the Center for Molecular Biomedicine (CMB), Jena 
      University Hospital, Jena, Germany.
FAU - Halle, Annett
AU  - Halle A
AUID- ORCID: 0000-0002-7204-3048
AD  - German Center for Neurodegenerative Diseases, DZNE, Bonn, Germany and Center of 
      Advanced European Studies and Research, Bonn, Germany.
FAU - van Echten-Deckert, Gerhild
AU  - van Echten-Deckert G
AUID- ORCID: 0000-0002-2816-7852
AD  - LIMES Institute, Membrane Biology & Lipid Biochemistry, University of Bonn, 
      Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190624
PL  - United States
TA  - Glia
JT  - Glia
JID - 8806785
RN  - 0 (Interleukin-6)
RN  - 0 (Sphingosine-1-Phosphate Receptors)
RN  - 0 (Tnf protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (interleukin-6, mouse)
RN  - 0 (sphingosine-1-phosphate receptor-2, mouse)
RN  - EC 4.1.2.- (Aldehyde-Lyases)
RN  - EC 4.1.2.27 (Sgpl1 protein, mouse)
SB  - IM
MH  - Aldehyde-Lyases/antagonists & inhibitors/genetics/*metabolism
MH  - Animals
MH  - Autophagy/*physiology
MH  - Cells, Cultured
MH  - Cerebral Cortex/metabolism/pathology
MH  - Inflammation/*metabolism/pathology
MH  - Interleukin-6/metabolism
MH  - Mice, Transgenic
MH  - Microglia/*metabolism/pathology
MH  - Sphingosine-1-Phosphate Receptors/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
OTO - NOTNLM
OT  - autophagy
OT  - inflammation
OT  - microglia
OT  - sphingosine 1-phosphate
EDAT- 2019/06/25 06:00
MHDA- 2020/03/17 06:00
CRDT- 2019/06/25 06:00
PHST- 2018/09/10 00:00 [received]
PHST- 2019/06/04 00:00 [revised]
PHST- 2019/06/05 00:00 [accepted]
PHST- 2019/06/25 06:00 [pubmed]
PHST- 2020/03/17 06:00 [medline]
PHST- 2019/06/25 06:00 [entrez]
AID - 10.1002/glia.23663 [doi]
PST - ppublish
SO  - Glia. 2019 Oct;67(10):1859-1872. doi: 10.1002/glia.23663. Epub 2019 Jun 24.