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IFNgamma enhances microglial reactions to hippocampal axonal degeneration
M B Jensen1, I V Hegelund, N D Lomholt
1Department of Anatomy and Neurobiology, University of Southern Denmark/Odense University, Odense C, DK 5000 Denmark.
Abstract:
Glial reactivity is implicated in CNS repair and regenerative responses. Microglia, the cells responding earliest to axonal injury, produce tumor necrosis factor-alpha (TNFalpha), a cytokine with both cytopathic and neuroprotective effects. We have studied activation of hippocampal microglia to produce TNFalpha in response to transection of perforant path axons in SJL/J mice. TNFalpha mRNA was produced in a transient manner, peaking at 2 d and falling again by 5 d after lesioning. This was unlike other markers of glial reactivity, such as Mac-1 upregulation, which were sustained over longer time periods. Message for the immune cytokine interferon-gamma (IFNgamma) was undetectable, and glial reactivity to axonal lesions occurred as normal in IFNgamma-deficient mice. Microglial responses to lesion-induced neuronal injury were markedly enhanced in myelin basic protein promoter-driven transgenic mice, in which IFNgamma was endogenously produced in hippocampus. The kinetics of TNFalpha downregulation 5 d after lesion was not affected by transgenic IFNgamma, indicating that IFNgamma acts as an amplifier and not an inducer of response. These results are discussed in the context of a regenerative role for TNFalpha in the CNS, which is innately regulated and potentiated by IFNgamma.
Insights
Glial cells in the brain produce tumor necrosis factor-alpha (TNFalpha) after injury. Interferon-gamma (IFNgamma) amplifies this response, suggesting a role in CNS repair.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Glial reactivity is crucial for central nervous system (CNS) repair.
- Microglia are early responders to axonal injury, producing tumor necrosis factor-alpha (TNFalpha).
- TNFalpha exhibits both damaging and protective effects in the CNS.
Purpose of the Study:
- To investigate the activation of hippocampal microglia and TNFalpha production following axonal injury.
- To determine the role of interferon-gamma (IFNgamma) in regulating microglial responses and TNFalpha production.
Main Methods:
- Transection of perforant path axons in SJL/J mice.
- Analysis of TNFalpha mRNA expression kinetics.
- Assessment of Mac-1 upregulation as a marker of glial reactivity.
- Comparison of wild-type and IFNgamma-deficient mice.
- Utilizing transgenic mice with endogenous IFNgamma production in the hippocampus.
Main Results:
- TNFalpha mRNA production peaked at 2 days post-lesion and decreased by 5 days, showing transient expression.
- Other glial reactivity markers, like Mac-1, remained elevated for longer periods.
- Glial reactivity to axonal lesions was normal in IFNgamma-deficient mice.
- Microglial responses were significantly enhanced in transgenic mice with endogenous IFNgamma production.
- IFNgamma amplified, but did not induce, the TNFalpha response, as downregulation kinetics remained unaffected.
Conclusions:
- TNFalpha production by microglia is transiently regulated after axonal injury.
- Endogenous IFNgamma potentiates microglial responses to CNS injury.
- These findings support a regenerative role for TNFalpha in the CNS, modulated by IFNgamma.