Proteolytic activation of monocyte chemoattractant protein-1 by plasmin underlies excitotoxic neurodegeneration in mice.
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.
Sheehan
John J
JJ
Department of Pharmacological Sciences and Program in Molecular and Cellular Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651, USA.
Zhou
Chun
C
Gravanis
Iordanis
I
Rogove
Andrew D
AD
Wu
Yan-Ping
YP
Bogenhagen
Daniel F
DF
Tsirka
Stella E
SE
D000704:Analysis of Variance; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000172:deficiency / Q000187:drug effects* / Q000378:metabolism*; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005341:Fibrinolysin / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D007608:Kainic Acid; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection
D000943:Antigens, Differentiation; D018932:Chemokine CCL2; D005343:Fibrinolytic Agents; C036763:monocyte-macrophage differentiation antigen; D049452:Green Fluorescent Proteins; D005341:Fibrinolysin; D008239:Lysine; D007608:Kainic Acid