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

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 7

In mice with chronic EAE, intraventricularly injected MG(IL-4) significantly improves clinical features and induces oligodendrogenesis.

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In mice with chronic EAE, intraventricularly injected MG(IL...
Spinal cords were excised 12 days after the last BrdU injection. (A and B) EAE scores in mice injected with either MG(IL-4) or PBS (n = 15 per group). *P < 0.05, **P < 0.01; Student’s t test. (C and D) Lack of beneficial effect of MG(–). In an independent experiment, mice with EAE were injected with MG(IL-4) (n = 7), MG(–) (n = 7), or PBS (n = 6) on day 10 after MOG vaccination. *P < 0.05, **P < 0.01, ***P < 0.001, MG(–) versus MG(IL-4); Student’s t test. ANOVA revealed no significant effect of MG(–) injection relative to PBS injection, whereas MG(IL-4) had a significant effect. Shown are (A and C) mean α SEM and (B and D) individual EAE scores on day 17. (E) NG2+ and RIP+ cells colabeled with BrdU+ cells were quantitatively analyzed at 300-μm intervals in both gray matter and white matter of the spinal cord (n = 4 per group). Data are mean α SEM. *P < 0.05 versus PBS; 2-tailed Student’s t test. (F) Representative confocal images of longitudinal sections of spinal cords stained with BrdU and costained for NG2 and RIP 34 days after immunization in MG(IL-4)- and PBS-treated mice. Separate confocal channels are shown in 2 right panels. (G) Newly formed oligodendrocytes were identifiable by colocalization of BrdU, NG2, and RIP in the white matter of MG(IL-4)-treated mice.