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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-alpha , IL-1beta , IFN-gamma , 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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