http://www.jneurosci.org/cgi/content/abstract/22/24/10633
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The Journal of Neuroscience, December 15, 2002,
22(24):10633-10642
Departments of 1 Neurosciences and 2 Immunology, Lerner
Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, 3 Gladstone
Institute of Cardiovascular Disease and Department of Medicine, University of
California San Francisco, San Francisco, California 94143, and 4 Department
of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston,
Massachusetts 02115
In this report we describe pertussis toxin-induced reversible encephalopathy
dependent on monocyte chemoattractant protein-1 (MCP-1)
overexpression (PREMO), a novel animal model that exhibits features
of human encephalopathic complications of inflammatory disorders such
as viral meningoencephalitis and Lyme neuroborreliosis as well as the
mild toxic encephalopathy that commonly precedes relapses of multiple
sclerosis (MS). Overexpression of the mouse MCP-1 gene product
(classically termed JE) in astrocytes, the major physiological CNS
cellular source of MCP-1, failed to induce neurological impairment.
Unexpectedly, transgenic (tg) mice overexpressing MCP-1 at a high
level (MCP-1hi) manifested transient, severe encephalopathy
with high mortality after injections of pertussis toxin (PTx)
plus complete Freund's adjuvant (CFA). Surviving mice showed markedly
improved function and did not relapse during a prolonged period of
observation. Tg mice that expressed lower levels of MCP-1 were
affected minimally after CFA/PTx injections, and tg expression of
other chemokines failed to elicit this disorder. The disorder was
significantly milder in mice lacking T-cells, which therefore play a
deleterious role in this encephalopathic process. Disruption of CC
chemokine receptor 2 (CCR2) abolished both CNS inflammation and
encephalopathy, identifying CCR2 as a relevant receptor for this
disorder. Proinflammatory and type 1 cytokines including TNF-
,
IL-1
, IFN-
,
IL-2, RANTES, and IP-10 were elevated in CNS tissues from mice with
PREMO. These studies characterize a novel model of reversible
inflammatory encephalopathy that is dependent on both genetic and
environmental factors.
Key words: chemokines; chemokine receptors; mice; gene targeting; macrophages; pertussis toxin
Copyright © 2002 Society for Neuroscience 0270-6474/02/222410633-10$05.00/0
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