title: Experimental autoimmune encephalomyelitis repressed by microglial paralysis.
abstract: 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.
authors.affiliation: Institute of Neuropathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Heppner
authors.forename: Melanie
authors.initials: M
authors.lastname: Greter
authors.forename: Denis
authors.initials: D
authors.lastname: Marino
authors.forename: Jeppe
authors.initials: J
authors.lastname: Falsig
authors.forename: Gennadij
authors.initials: G
authors.lastname: Raivich
authors.forename: Nadine
authors.initials: N
authors.lastname: Hövelmeyer
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002678:Chimera / Q000235:genetics / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D005154:Facial Nerve / Q000166:cytology; D015774:Ganciclovir / Q000008:administration & dosage / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D039481:CD11b Antigen; D011993:Recombinant Fusion Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir