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Article
Nature Medicine  11, 146 - 152 (2005)
Published online: 23 January 2005; | doi:10.1038/nm1177

Experimental autoimmune encephalomyelitis repressed by microglial paralysis

Frank L Heppner1, Melanie Greter1, 2, Denis Marino1, Jeppe Falsig1, Gennadij Raivich3, Nadine Hövelmeyer4, Ari Waisman4, Thomas Rülicke5, Marco Prinz1, 7, Josef Priller6, Burkhard Becher2 & Adriano Aguzzi1

1  Institute of Neuropathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.

2  Department Neurology, Neuroimmunology Unit, University Hospital Zurich, CH-8091 Zurich, Switzerland.

3  Perinatal Brain Repair Group, Department of Obstetrics and Gynaecology and Department of Anatomy, University College London, WC1E 6HX London, UK.

4  Laboratory for Molecular Immunology, Institute for Genetics, University of Cologne, D-50931 Cologne, Germany.

5  Institute of Laboratory Animal Science, University of Zurich, CH-8091 Zurich, Switzerland.

6  Departments of Psychiatry and Experimental Neurology, Charité, Humboldt-University Berlin, 10117 Berlin, Germany.

7  Present address: Institute of Neuropathology, Georg-August-University Göttingen, D-37075 Göttingen, Germany.

Correspondence should be addressed to Adriano Aguzzi adriano@pathol.unizh.ch
Although microglial activation occurs in inflammatory, degenerative and neoplastic central nervous system (CNS) disorders, its role in pathogenesis is unclear. We studied this question by generating CD11b-HSVTK transgenic mice, which express herpes simplex thymidine kinase in macrophages and microglia. Ganciclovir treatment of organotypic brain slice cultures derived from CD11b-HSVTK mice abolished microglial release of nitrite, proinflammatory cytokines and chemokines. Systemic ganciclovir administration to CD11b-HSVTK mice elicited hematopoietic toxicity, which was prevented by transfer of wild-type bone marrow. In bone marrow chimeras, ganciclovir blocked microglial activation in the facial nucleus upon axotomy and repressed the development of experimental autoimmune encephalomyelitis. We conclude that microglial paralysis inhibits the development and maintenance of inflammatory CNS lesions. The microglial compartment thus provides a potential therapeutic target in inflammatory CNS disorders. These results validate CD11b-HSVTK mice as a tool to study the impact of microglial activation on CNS diseases in vivo.

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ISSN: 1078-8956
EISSN: 1546-170X
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