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GSK3β Inhibition by Phosphorylation at Ser389 Controls Neuroinflammation.

Belen Calvo1, Miriam Fernandez1, Mercedes Rincon2

  • 1Research Institute for Neurological Disabilities (IDINE), Albacete Medical School, University of Castilla-La Mancha (UCLM), 02008 Albacete, Spain.

International Journal of Molecular Sciences
|January 8, 2023
PubMed
Summary

Impaired Glycogen Synthase Kinase 3 β (GSK3β) Ser389 phosphorylation leads to sustained neuroinflammation. This study reveals GSK3β Ser389 inactivation controls brain immune responses, impacting neuroinflammatory diseases.

Keywords:
NF-κB signalingastrocytesflow cytometrymicroglianeuroinflammationneutrophils

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Area of Science:

  • Neuroimmunology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Glycogen Synthase Kinase 3 β (GSK3β) regulates immune responses via Ser9 phosphorylation.
  • The role of alternative GSK3β inhibition, specifically Ser389 phosphorylation, in neuroinflammation is largely unknown.

Purpose of the Study:

  • To investigate the impact of impaired GSK3β Ser389 phosphorylation on neuroinflammation using a knock-in mouse model.
  • To elucidate the specific signaling pathways affected by this regulatory mechanism.

Main Methods:

  • Utilized GSK3β Ser389 knock-in (KI) mice and compared them to wild-type (WT) C57BL/6J counterparts.
  • Analyzed glial cell activation, immune cell infiltration in the brain, and phosphorylation of key signaling molecules (IKK, STAT3) following lipopolysaccharide (LPS) challenge.
  • Assessed peripheral immune responses to confirm brain-specific effects.

Main Results:

  • GSK3β Ser389 KI mice exhibited increased microglia/macrophage activation, astrocyte elevation, and neutrophil infiltration, indicating sustained low-grade neuroinflammation.
  • Glial activation and immune cell infiltration in response to LPS were significantly impaired in GSK3β Ser389 KI mice.
  • NF-κB signaling, indicated by failed IKK phosphorylation, was specifically disrupted, while STAT3 phosphorylation remained intact, highlighting a brain-specific effect on this pathway.

Conclusions:

  • GSK3β inactivation via Ser389 phosphorylation is a critical regulator of the brain's inflammatory response.
  • Dysregulation of this pathway contributes to sustained neuroinflammation and impaired acute responses.
  • Targeting GSK3β Ser389 phosphorylation may offer therapeutic strategies for neuroinflammatory diseases.