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Published on: February 5, 2015
Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple
Oleg Butovsky1, Gennady Landa, Gilad Kunis
1Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
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-gamma (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-alpha production, and overcame blockage of IGF-I production caused by IFN-gamma. 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.
Insights
High levels of interferon-gamma (IFN-γ) impair neural stem cell differentiation in rodents. However, interleukin-4 (IL-4) activated microglia promote oligodendrocyte regeneration and improve symptoms in demyelinating diseases.
Area of Science:
- Neuroscience
- Immunology
- Stem Cell Biology
Background:
- The role of activated microglia (MG) in demyelinating diseases like multiple sclerosis remains debated.
- Interferon-gamma (IFN-γ), a cytokine linked to autoimmune conditions, influences microglial function.
Purpose of the Study:
- To investigate the impact of IFN-γ on microglial function and oligodendrogenesis.
- To explore the potential of IL-4 activated microglia in promoting central nervous system repair.
Main Methods:
- Rodent models of demyelinating disease (EAE) were used.
- Microglia were activated with varying levels of IFN-γ and IL-4.
- The effect on neural stem/progenitor cell oligodendrogenesis was assessed.
- IL-4 activated microglia were administered intrathecally.
Main Results:
- High IFN-γ levels induced a microglial phenotype that inhibited oligodendrogenesis.
- IL-4 reversed this inhibition, reduced TNF-α, and restored IGF-I production.
- Intrathecal administration of IL-4 activated MG increased oligodendrogenesis and improved clinical signs in EAE rodents.
- Newly formed oligodendrocytes were found near MG expressing MHC class II and IGF-I.
Conclusions:
- Microglia activated by IL-4 can promote oligodendrogenesis from endogenous stem cells.
- This suggests a novel therapeutic strategy for demyelinating diseases by modulating microglial function.
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