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.
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Acknowledgements
We thank D.G. Tenen for providing Itgam-Thy1-hGH cDNA, T. Bush for supplying GFAP-HSVTK control brains, C. Weissmann for discussion, J. Weber, P. Schwarz, A. Schifferli, M. König for technical assistance and C. Sigurdson for critical comments on the manuscript. This work is supported by grants of the Bundesamt für Bildung und Wissenschaft (EU), the Swiss National Foundation, the US National Prion Research Program, and the National Center of Competence in Research (NCCR) on neural plasticity and repair to A.A. F.L.H. was supported by the Human Frontier Science Program (HFSP), the Stammbach and the Leopoldina foundations. M.G. is a fellow of the Roche Research Foundation of Switzerland. B.B. is a Harry Weaver Neuroscience Scholar of the US National Multiple Sclerosis Society (NMSS).
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Supplementary information
Supplementary Fig. 1
GCV-mediated myelotoxicity of tg620 mice. (PDF 209 kb)
Supplementary Fig. 2
Intact blood-brain barrier of tg620chi mice. (PDF 1607 kb)
Supplementary Fig. 3
Reduced microglial numbers in tg620chi mice upon chronic GCV treatment. (PDF 56 kb)
Supplementary Fig. 4
GCV-mediated inhibition of microglial activation in brain slices of tg620 mice. (PDF 65 kb)
Supplementary Fig. 5
tg620 and wild-type mice exhibit similar EAE phenotype. (PDF 32 kb)
Supplementary Fig. 6
Encephalitogenic T cells of GCV-treated tg620chi mice are fully responsive upon MOG recall. (PDF 48 kb)
Supplementary Fig. 7
No obvious difference in microglial recruitment upon GCV treatment in MOG-immunized tg620chi mice. (PDF 71 kb)
Supplementary Table 1
GCV-mediated aplastic anemia of tg620 mice (PDF 15 kb)
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Heppner, F., Greter, M., Marino, D. et al. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11, 146–152 (2005). https://doi.org/10.1038/nm1177
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DOI: https://doi.org/10.1038/nm1177
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