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Published on: April 13, 2017
Priming of microglia by type II interferon is lasting and resistant to modulation by interleukin-10 in situ
Marc Hemmerich1, Nikolai Malorny1, Andrea Lewen1
1Institute of Physiology and Pathophysiology, University of Heidelberg, D-69120 Heidelberg, Germany.
Abstract:
Immunological priming by type II interferon (IFN-γ) is crucial for evoking neurotoxic phenotypes of microglia (tissue-resident macrophages). We report that serial exposure of hippocampal slice cultures to IFN-γ and lipopolysaccharide (Toll-like receptor 4 ligand) induces high release of IL-6, TNF-α and nitric oxide, concomitant loss of electrical network activity (neuronal gamma oscillations) and neurodegeneration. Notably, these effects are still present after 3 days of IFN-γ removal but neither mimicked by IFN-α nor attenuated by anti-inflammatory cytokine, IL-10. Our findings might be relevant for brain diseases featuring elevated IFN-γ levels, such as viral and bacterial infections, multiple sclerosis and Alzheimer's disease.
Insights
Type II interferon (IFN-γ) primes microglia to become neurotoxic. Serial exposure to IFN-γ and lipopolysaccharide causes neuronal damage and network dysfunction, persisting even after IFN-γ removal, suggesting relevance for neuroinflammatory diseases.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Cellular Neuroscience
Background:
- Microglia, the brain's resident macrophages, play a critical role in immune responses.
- Type II interferon-gamma (IFN-γ) is known to modulate microglial function.
- Neuroinflammation is implicated in the pathology of various neurological disorders.
Purpose of the Study:
- To investigate the effects of sequential exposure to IFN-γ and lipopolysaccharide (LPS) on microglial activation and neuronal function.
- To determine the persistence of IFN-γ-induced microglial changes and their impact on neuronal network activity.
- To explore the potential therapeutic implications for IFN-γ-associated neurological diseases.
Main Methods:
- Utilized hippocampal slice cultures for in vitro experimentation.
- Administered serial exposures of IFN-γ and LPS (a Toll-like receptor 4 ligand).
- Measured cytokine release (IL-6, TNF-α), nitric oxide production, neuronal network activity (gamma oscillations), and neurodegeneration.
Main Results:
- Serial IFN-γ and LPS exposure induced significant release of IL-6, TNF-α, and nitric oxide.
- This exposure led to a loss of neuronal gamma oscillations and observable neurodegeneration.
- These detrimental effects persisted for at least 3 days after IFN-γ removal and were not replicated by IFN-α or mitigated by IL-10.
Conclusions:
- IFN-γ priming is critical for inducing neurotoxic microglial phenotypes.
- Sustained microglial activation and neurotoxicity can occur following IFN-γ exposure, impacting neuronal function.
- Findings are relevant to brain diseases characterized by elevated IFN-γ, including infections, multiple sclerosis, and Alzheimer's disease.
