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Published on: December 8, 2017
Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity
Christopher J Yuskaitis1, Richard S Jope
1Department of Psychiatry and Behavioral Neurobiology, 1720 Seventh Avenue South, Sparks Center 1057, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
Abstract:
Microglia play a prominent role in the brain's inflammatory response to injury or infection by migrating to affected locations, secreting inflammatory molecules, and phagocytosing damaged tissue. However, because severe or chronic neuroinflammation exacerbates many neurological conditions, controlling microglia actions may provide therapeutic benefits in a diverse array of diseases. Since glycogen synthase kinase-3 (GSK3) promotes inflammatory responses in peripheral immune cells, we investigated if inhibitors of GSK3 attenuated microglia responses to inflammatory stimuli. Treatment of BV-2 microglia with GSK3 inhibitors greatly reduced the migration of microglia in both a scratch assay and in a transwell migration assay. Treatment of BV-2 microglia with lipopolysaccharide (LPS) stimulated the production of interleukin-6 and increased the expression of inducible nitric oxide synthase (iNOS) and NO production. Each of these microglia responses to inflammatory stimulation were greatly attenuated by GSK3 inhibitors. However, GSK3 inhibitors did not cause a general impairment of microglia functions, as the LPS-induced stimulated expression of cyclooxygenase-2 was unaltered. Regulation of microglia functions were also evident in cultured mouse hippocampal slices where GSK3 inhibitors reduced cytokine production and microglial migration, and provided protection from inflammation-induced neuronal toxicity. These findings demonstrate that GSK3 promotes microglial responses to inflammation and that the utilization of GSK3 inhibitors provides a means to limit the inflammatory actions of microglia.
Insights
Glycogen synthase kinase-3 (GSK3) inhibitors reduce harmful microglia inflammatory responses, including migration and cytokine production. This suggests GSK3 inhibitors may offer therapeutic benefits for neurological diseases by controlling neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglia are key immune cells in the brain, orchestrating inflammatory responses to injury and infection.
- Chronic or severe neuroinflammation is implicated in numerous neurological disorders.
- Glycogen synthase kinase-3 (GSK3) is known to promote inflammatory responses in peripheral immune cells.
Purpose of the Study:
- To investigate the role of GSK3 in microglia inflammatory responses.
- To determine if GSK3 inhibitors can attenuate microglia activation and associated neuroinflammation.
Main Methods:
- Utilized BV-2 microglia cell line and cultured mouse hippocampal slices.
- Employed scratch and transwell assays to assess microglia migration.
- Stimulated microglia with lipopolysaccharide (LPS) to induce inflammatory responses.
- Administered GSK3 inhibitors to evaluate their effects on microglia activation, cytokine production, and neuronal toxicity.
Main Results:
- GSK3 inhibitors significantly reduced microglia migration in vitro.
- Inhibitors attenuated LPS-induced production of interleukin-6 and nitric oxide (NO) via inducible nitric oxide synthase (iNOS) expression.
- GSK3 inhibition did not broadly impair microglia function, as cyclooxygenase-2 expression remained unaffected.
- In hippocampal slices, GSK3 inhibitors reduced cytokine production, microglial migration, and protected neurons from inflammation-induced toxicity.
Conclusions:
- GSK3 plays a critical role in promoting microglia inflammatory responses.
- GSK3 inhibitors effectively limit detrimental microglia activities, such as migration and cytokine release.
- Targeting GSK3 represents a potential therapeutic strategy for managing neuroinflammation in various neurological conditions.
