QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, February 14, 2007, 27(7):1738-1745; doi:10.1523/JNEUROSCI.4987-06.2007

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Sheehan, J. J. Articles by Tsirka, S. E. Search for Related Content PubMed PubMed Citation Articles by Sheehan, J. J. Articles by Tsirka, S. E.

 Previous Article  |  Next Article 

Cellular/Molecular
Proteolytic Activation of Monocyte Chemoattractant Protein-1 by Plasmin Underlies Excitotoxic Neurodegeneration in Mice

John J. Sheehan, Chun Zhou, Iordanis Gravanis, Andrew D. Rogove, Yan-Ping Wu, Daniel F. Bogenhagen, and Stella E. Tsirka

Department of Pharmacological Sciences and Program in Molecular and Cellular Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651

Correspondence should be addressed to Stella E. Tsirka at the above address. Email: stella{at}pharm.stonybrook.edu

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.

Key words: MCP-1; plasmin; excitotoxicity; microglia; mice; neurodegeneration

---

Received Sept. 5, 2006; revised Jan. 2, 2007; accepted Jan. 2, 2007.

Correspondence should be addressed to Stella E. Tsirka at the above address. Email: stella{at}pharm.stonybrook.edu

This article has been cited by other articles:

				P. J. Cimino, I. Sokal, J. Leverenz, Y. Fukui, and T. J. Montine DOCK2 Is a Microglial Specific Regulator of Central Nervous System Innate Immunity Found in Normal and Alzheimer's Disease Brain Am. J. Pathol., October 1, 2009; 175(4): 1622 - 1630. [Abstract] [Full Text] [PDF]

				A. L. Samson, R. J. Borg, B. Niego, C. H. Y. Wong, P. J. Crack, T. Yongqing, and R. L. Medcalf A nonfibrin macromolecular cofactor for tPA-mediated plasmin generation following cellular injury Blood, August 27, 2009; 114(9): 1937 - 1946. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help