PMID- 25443158
OWN - NLM
STAT- MEDLINE
DCOM- 20160219
LR  - 20150602
IS  - 1440-1789 (Electronic)
IS  - 0919-6544 (Linking)
VI  - 35
IP  - 3
DP  - 2015 Jun
TI  - Activated microglia in ischemic stroke penumbra upregulate MCP-1 and CCR2 
      expression in response to lysophosphatidylcholine derived from adjacent neurons 
      and astrocytes.
PG  - 209-23
LID - 10.1111/neup.12182 [doi]
AB  - In acute stage of ischemic stroke, the surrounding zone of fresh infarcts is 
      termed penumbra, where microglia are activated in response to damaged 
      cell-derived proinflammatory mediators. Rescuing penumbra by regulating 
      inflammatory activity would minimize infarct volume, which positively correlates 
      with functional outcome. To elucidate mechanisms by which inflammation occurs in 
      penumbra, we performed immunohistochemical investigations using autopsied human 
      brains affected by acute, subacute and chronic stages of cerebral infarction as 
      well as cell culture experiments using a murine microglia-derived cell line 
      (BV-2). In penumbra of fresh infarcts, immunoreactivity for secretory 
      phospholipase A2 group X (sPLA2 -X), which is responsible for the production and 
      release of the proinflammatory mediator lysophosphatidylcholine (LPC), was 
      intensely detected in neurons and astrocytes. Furthermore, immunoreactivities for 
      the LPC receptors G protein-coupled receptor 132 (G2A) and P2X purinoreceptor 7 
      (P2X7R), as well as the CC chemokine monocyte chemoattractant protein-1 (MCP-1) 
      and its receptor CCR2, were detectable in activated microglia. Prior to cell 
      culture experiments, it was confirmed that BV-2 cells were immunoreactive for 
      ionized Ca(2+) -binding adaptor molecule 1 (Iba1), G2A, P2X7R, MCP-1 and CCR2. 
      Reverse transcription-quantitative polymerase chain reaction analysis revealed 
      that MCP-1 and CCR2 mRNA expression levels were significantly increased by LPC 
      stimulation. The LPC-driven increase in MCP-1 transcripts was lowered by blockade 
      of G2A or P2X7R or by inhibition of Rho-associated protein kinase (ROCK) or 
      inhibitor of kappaBalpha kinase. The LPC-driven increase in CCR2 transcripts was lowered 
      by blockade of G2A or P2X7R or by inhibition of ROCK, phosphatidylinositide 
      3-kinanse, extracellular signal-regulated kinase kinase, or p38 mitogen-activated 
      protein kinase. The present results provide in vivo and in vitro evidence that in 
      acute stage of ischemic stroke, the sPLA2 -X enzyme product LPC is released from 
      neurons and astrocytes and stimulates penumbra microglia via G2A and P2X7R, 
      thereby exerting the MCP-1/CCR2-mediated neurotoxicity through distinct 
      cell-signaling pathways.
CI  - (c) 2014 Japanese Society of Neuropathology.
FAU - Inose, Yuri
AU  - Inose Y
AD  - Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
AD  - Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
AD  - Department of Neurology, Tokyo Women's Medical University, Tokyo, Japan.
FAU - Kato, Yoichiro
AU  - Kato Y
AD  - Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
FAU - Kitagawa, Kazuo
AU  - Kitagawa K
AD  - Department of Neurology, Tokyo Women's Medical University, Tokyo, Japan.
FAU - Uchiyama, Shinichiro
AU  - Uchiyama S
AD  - Department of Neurology, Tokyo Women's Medical University, Tokyo, Japan.
AD  - Clinical Research Center for Medicine, International University of Health and 
      Welfare, Tokyo, Japan.
AD  - Center for Brain and Cerebral Vessels, Sanno Hospital and Sanno Medical Center, 
      Tokyo, Japan.
FAU - Shibata, Noriyuki
AU  - Shibata N
AD  - Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
LA  - eng
PT  - Journal Article
DEP - 20141202
PL  - Australia
TA  - Neuropathology
JT  - Neuropathology : official journal of the Japanese Society of Neuropathology
JID - 9606526
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Ccr2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Lysophosphatidylcholines)
RN  - 0 (Receptors, CCR2)
RN  - EC 3.1.1.4 (Group X Phospholipases A2)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Animals
MH  - Astrocytes/metabolism
MH  - Brain Ischemia/*metabolism/pathology
MH  - Cell Line
MH  - Chemokine CCL2/metabolism
MH  - Encephalitis/*metabolism
MH  - Female
MH  - Group X Phospholipases A2/metabolism
MH  - Humans
MH  - Lysophosphatidylcholines/metabolism
MH  - Male
MH  - Mice
MH  - Microglia/*metabolism
MH  - Middle Aged
MH  - Neurons/metabolism
MH  - Receptors, CCR2/metabolism
MH  - Signal Transduction
MH  - Stroke/*metabolism/pathology
MH  - Up-Regulation
OTO - NOTNLM
OT  - MCP-1
OT  - ischemic penumbra
OT  - lysophophatidylcholine
OT  - microglia
OT  - phospholipase A2
EDAT- 2014/12/03 06:00
MHDA- 2016/02/20 06:00
CRDT- 2014/12/03 06:00
PHST- 2014/09/26 00:00 [received]
PHST- 2014/10/16 00:00 [revised]
PHST- 2014/10/17 00:00 [accepted]
PHST- 2014/12/03 06:00 [entrez]
PHST- 2014/12/03 06:00 [pubmed]
PHST- 2016/02/20 06:00 [medline]
AID - 10.1111/neup.12182 [doi]
PST - ppublish
SO  - Neuropathology. 2015 Jun;35(3):209-23. doi: 10.1111/neup.12182. Epub 2014 Dec 2.