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The Journal of Neuroscience, December 15, 2002, 22(24):10633-10642
Pertussis Toxin-Induced Reversible Encephalopathy Dependent on
Monocyte Chemoattractant Protein-1 Overexpression in Mice
DeRen
Huang1,
Marie
Tani1,
Jintang
Wang1,
Yulong
Han1,
Toby T.
He1,
Jennifer
Weaver1,
Israel F.
Charo3,
Vincent K.
Tuohy2,
Barrett J.
Rollins4, and
Richard M.
Ransohoff1
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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