Highlights
- •Fasudil reduces inflammatory cytokines and chemokines in cultured astrocytes.
- •Fasudil reduces infiltration and accumulation of pathogenic T cells into the CNS.
- •The expression of CCL-20 on astrocytes was inhibited in Fasudil-treated EAE.
- •Fasudil declines astrocyte chemokine-mediated infiltration of pathogenic T cells.
Abstract
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis
(EAE), are autoimmune diseases characterized by the immune-mediated demyelination
and neurodegeneration of the CNS. Our previous studies showed that Rho kinase inhibitor
Fasudil can delay onset, and ameliorate severity of EAE, accompanied by the improvement
in myelination and the inhibition of inflammatory responses in the CNS. In this study,
we found that Fasudil inhibited the migration of T cells indirectly by affecting the
production of inflammatory factors and the expression of chemokines in astrocytes
functions, indicating that Fasudil treatment reduced inflammatory cytokines such as
TNF-α and IL-6, reactive oxygen species (NO) and chemokines like MIP-3α (CCL-20),
RANTES (CCL5), MIP-1α (CCL-3) and MCP-1 (CCL2) in vitro, and blocked the chemotaxis
of reactive mononuclear cells in EAE mice. Further studies found that Fasudil treatment
reduced the infiltration and accumulation of pathogenic T cells into the CNS. Astrocytes
expressing GFAP and CCL-20 were inhibited in Fasudil-treated EAE compared with control
mice. These results demonstrate that Fasudil alleviates the pathogenesis of EAE possibly
by blocking astrocyte-derived chemokine-mediated migration of inflammatory macrophages
and pathogenic T cells, and might be used to treat MS.
Keywords
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Article info
Publication history
Published online: May 26, 2014
Accepted:
May 14,
2014
Received in revised form:
April 17,
2014
Received:
November 7,
2013
Identification
Copyright
© 2014 Published by Elsevier Inc.
