PMID- 17301181
OWN - NLM
STAT- MEDLINE
DCOM- 20070313
LR  - 20200225
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 27
IP  - 7
DP  - 2007 Feb 14
TI  - Proteolytic activation of monocyte chemoattractant protein-1 by plasmin underlies 
      excitotoxic neurodegeneration in mice.
PG  - 1738-45
AB  - Exposure of neurons to high concentrations of excitatory neurotransmitters causes 
      them to undergo excitotoxic death via multiple synergistic injury mechanisms. One 
      of these mechanisms involves actions undertaken locally by microglia, the 
      CNS-resident macrophages. Mice deficient in the serine protease plasmin exhibit 
      decreased microglial migration to the site of excitatory neurotransmitter release 
      and are resistant to excitotoxic neurodegeneration. Microglial chemotaxis can be 
      signaled by the chemokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 (CC 
      chemokine ligand 2). We show here that mice genetically deficient for MCP-1 
      phenocopy plasminogen deficiency by displaying decreased microglial recruitment 
      and resisting excitotoxic neurodegeneration. Connecting these pathways, we 
      demonstrate that MCP-1 undergoes a proteolytic processing step mediated by 
      plasmin. The processing, which consists of removal of the C terminus of MCP-1, 
      enhances the potency of MCP-1 in in vitro migration assays. Finally, we show that 
      infusion of the cleaved form of MCP-1 into the CNS restores microglial 
      recruitment and excitotoxicity in plasminogen-deficient mice. These findings 
      identify MCP-1 as a key downstream effector in the excitotoxic pathway triggered 
      by plasmin and identify plasmin as an extracellular chemokine activator. Finally, 
      our results provide a mechanism that explains the resistance of 
      plasminogen-deficient mice to excitotoxicity.
FAU - Sheehan, John J
AU  - Sheehan JJ
AD  - Department of Pharmacological Sciences and Program in Molecular and Cellular 
      Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651, USA.
FAU - Zhou, Chun
AU  - Zhou C
FAU - Gravanis, Iordanis
AU  - Gravanis I
FAU - Rogove, Andrew D
AU  - Rogove AD
FAU - Wu, Yan-Ping
AU  - Wu YP
FAU - Bogenhagen, Daniel F
AU  - Bogenhagen DF
FAU - Tsirka, Stella E
AU  - Tsirka SE
LA  - eng
GR  - 5R01ES01203904/ES/NIEHS NIH HHS/United States
GR  - 5R01NS04216804/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Antigens, Differentiation)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Fibrinolytic Agents)
RN  - 0 (monocyte-macrophage differentiation antigen)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 3.4.21.7 (Fibrinolysin)
RN  - K3Z4F929H6 (Lysine)
RN  - SIV03811UC (Kainic Acid)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Antigens, Differentiation/metabolism
MH  - Blotting, Western/methods
MH  - Cell Line
MH  - Cell Movement/drug effects
MH  - Chemokine CCL2/deficiency/*drug effects/*metabolism
MH  - Drug Interactions
MH  - Enzyme-Linked Immunosorbent Assay/methods
MH  - Fibrinolysin/*pharmacology
MH  - Fibrinolytic Agents/*pharmacology
MH  - Gene Expression Regulation/drug effects/physiology
MH  - Green Fluorescent Proteins/metabolism
MH  - Hippocampus/drug effects/metabolism
MH  - In Situ Nick-End Labeling/methods
MH  - Kainic Acid
MH  - Lysine/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Microglia/drug effects
MH  - Neurodegenerative Diseases/chemically induced/*metabolism/pathology
MH  - Time Factors
MH  - Transfection
PMC - PMC6673734
EDAT- 2007/02/16 09:00
MHDA- 2007/03/14 09:00
PMCR- 2007/08/14
CRDT- 2007/02/16 09:00
PHST- 2007/02/16 09:00 [pubmed]
PHST- 2007/03/14 09:00 [medline]
PHST- 2007/02/16 09:00 [entrez]
PHST- 2007/08/14 00:00 [pmc-release]
AID - 27/7/1738 [pii]
AID - 3188416 [pii]
AID - 10.1523/JNEUROSCI.4987-06.2007 [doi]
PST - ppublish
SO  - J Neurosci. 2007 Feb 14;27(7):1738-45. doi: 10.1523/JNEUROSCI.4987-06.2007.