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Published on: April 13, 2017
Interferon γ: a master cytokine in microglia-mediated neural network dysfunction and neurodegeneration
Oliver Kann1, Fadi Almouhanna2, Bruno Chausse2
1Institute of Physiology and Pathophysiology, University of Heidelberg, D-69120 Heidelberg, Germany; Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, D-69120 Heidelberg, Germany.
Abstract:
Traditionally, lymphocytic interferon γ (IFN-γ) was considered to be a simple 'booster' of proinflammatory responses by microglia (brain-resident macrophages) during bacterial or viral infection. Recent slice culture (in situ) and in vivo studies suggest, however, that IFN-γ has a unique role in microglial activation. Priming by IFN-γ results in proliferation (microgliosis), enhanced synapse elimination, and moderate nitric oxide release sufficient to impair synaptic transmission, gamma rhythm activity, and cognitive functions. Moreover, IFN-γ is pivotal for driving Toll-like receptor (TLR)-activated microglia into neurotoxic phenotypes that induce energetic and oxidative stress, severe network dysfunction, and neuronal death. Pharmacological targeting of activated microglia could be beneficial during elevated IFN-γ levels, blood-brain barrier leakage, and parenchymal T lymphocyte infiltration associated with, for instance, encephalitis, multiple sclerosis, and Alzheimer's disease.
Insights
Interferon gamma (IFN-γ) uniquely activates microglia, causing cognitive decline and neuronal death. Targeting these activated brain cells may benefit neuroinflammatory diseases like multiple sclerosis and Alzheimer's.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Interferon gamma (IFN-γ) was traditionally viewed as a pro-inflammatory mediator for microglia during infections.
- Emerging research indicates a more complex, unique role for IFN-γ in microglial activation and brain function.
Purpose of the Study:
- To elucidate the specific functions of IFN-γ in microglial activation beyond simple pro-inflammatory boosting.
- To investigate the consequences of IFN-γ-mediated microglial priming on neuronal networks and cognitive function.
Main Methods:
- In situ slice cultures and in vivo studies were employed to observe microglial responses.
- Analysis of microglial proliferation, synapse elimination, nitric oxide release, and network activity was performed.
Main Results:
- IFN-γ priming induces microgliosis, enhances synapse elimination, and impairs synaptic transmission and cognitive functions.
- IFN-γ drives Toll-like receptor-activated microglia towards neurotoxic phenotypes, causing oxidative stress, network dysfunction, and neuronal death.
Conclusions:
- IFN-γ plays a critical role in modulating microglial activity, leading to neurotoxic effects and cognitive impairment.
- Pharmacological targeting of activated microglia is a potential therapeutic strategy for conditions with elevated IFN-γ, such as encephalitis, multiple sclerosis, and Alzheimer's disease.
