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The Journal of Neuroscience, December 15, 2002, 22(24):10781-10789
Involvement of Tissue Plasminogen Activator in Onset and Effector
Phases of Experimental Allergic Encephalomyelitis
Weiquan
Lu1,
Madhuri
Bhasin2, and
Stella E.
Tsirka1, 2
Programs in 1 Pharmacology and 2 Genetics,
Department of Pharmacological Sciences, University Medical Center at
Stony Brook, Stony Brook, New York 11794-8651
Inflammation, demyelination, and neurodegeneration are
pathological features of multiple sclerosis (MS). In the brains of MS patients, tissue plasminogen activator (tPA) mRNA and protein are
upregulated, and changes in the levels of tPA correlate with progression of the disease. However, the role of tPA in MS is as yet
unknown. tPA functions in the CNS in neuronal plasticity and cell
death. tPA also mediates the activation of microglia, the CNS "immune
cells." In this study, we establish that tPA activity increases
during major oligodendrocyte glycoprotein-induced experimental allergic
encephalomyelitis (EAE) in normal mice. To explore the role of tPA in
this disease as a model for MS, we have examined the EAE course and
expression of histopathological markers in mice lacking tPA
(tPA /). We find that tPA/
mice have a delayed onset of EAE but then exhibit increased severity and delayed recovery from the neurological dysfunction. Demyelination and axon degeneration are delayed, microglial activation is attenuated, and the production of chemokines is decreased. Our results suggest that
tPA and activated microglia have complex roles in MS/EAE, and that
these roles are harmful during the onset of the disease but beneficial
in the recovery phase. A temporally restricted attenuation of tPA
activity could have therapeutic potential in the management of MS.
Key words:
proteolysis; multiple sclerosis; microglia; mice; plasmin; cytokine
Copyright © 2002 Society for Neuroscience 0270-6474/02/222410781-09$05.00/0
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