Experimental autoimmune encephalomyelitis repressed by microglial paralysis.
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.
Heppner
Frank L
FL
Institute of Neuropathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Greter
Melanie
M
Marino
Denis
D
Falsig
Jeppe
J
Raivich
Gennadij
G
Hövelmeyer
Nadine
N
Waisman
Ari
A
Rülicke
Thomas
T
Prinz
Marco
M
Priller
Josef
J
Becher
Burkhard
B
Aguzzi
Adriano
A
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
D000998:Antiviral Agents; D039481:CD11b Antigen; D011993:Recombinant Fusion Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir