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Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis
Oleg Butovsky, … , Steffen Jung, Michal Schwartz
Oleg Butovsky, … , Steffen Jung, Michal Schwartz
Published April 3, 2006
Citation Information: J Clin Invest. 2006;116(4):905-915. https://doi.org/10.1172/JCI26836.
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Research Article Neuroscience

Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis

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Abstract

The role of activated microglia (MG) in demyelinating neurodegenerative diseases such as multiple sclerosis is controversial. Here we show that high, but not low, levels of IFN-γ (a cytokine associated with inflammatory autoimmune diseases) conferred on rodent MG a phenotype that impeded oligodendrogenesis from adult neural stem/progenitor cells. IL-4 reversed the impediment, attenuated TNF-α production, and overcame blockage of IGF-I production caused by IFN-γ. In rodents with acute or chronic EAE, injection of IL-4–activated MG into the cerebrospinal fluid resulted in increased oligodendrogenesis in the spinal cord and improved clinical symptoms. The newly formed oligodendrocytes were spatially associated with MG expressing MHC class II proteins and IGF-I. These results point to what we believe to be a novel role for MG in oligodendrogenesis from the endogenous stem cell pool.

Authors

Oleg Butovsky, Gennady Landa, Gilad Kunis, Yaniv Ziv, Hila Avidan, Nadav Greenberg, Adi Schwartz, Igor Smirnov, Ayala Pollack, Steffen Jung, Michal Schwartz

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Figure 1

High-dose IFN-γ, by inducing TNF-α, inhibits the ability of MG to support oligodendrogenesis, whereas MG activated by IL-4 can overcome the inhibition.

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High-dose IFN-γ, by inducing TNF-α, inhibits the ability of MG to suppor...
(A) GFP-expressing NPCs (green) were cultured for 10 days without MG (control) or cocultured for 10 days with MG(IL-4), MG(IFN-γ, 10 ng/ml), MG(IFN-γ, 100 ng/ml), MG activated by both IFN-γ (100 ng/ml) and IL-4 (10 ng/ml), or MG(IFN-γ, 100 ng/ml) in the presence of anti–TNF-α (1 ng/ml). (B) Colocalization of GFP, NG2, and pre-ensheathing marker of oligodendrocytes RIP. Arrows show the same cells expressing the indicated markers. Arrowhead shows a highly branched GFP+/RIP+ oligodendrocyte. Separate confocal channels are shown in 2 right panels. (C) Quantification of NG2+ or RIP+ cells (expressed as a percentage of GFP+ cells) obtained from confocal images. Data are from 2 independent experiments in replicate cultures; bars represent mean α SD. *P < 0.05, **P < 0.01, ***P < 0.001 versus control (2-tailed Student’s t test). The P values indicated in the figure represent a comparison of the groups as analyzed by ANOVA.
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