GSK3ß Inhibition by Phosphorylation at Ser389 Controls Neuroinflammation.

ABSTRACT

The inhibition of Glycogen Synthase Kinase 3 ß (GSK3ß) by Ser9 phosphorylation affects many physiological processes, including the immune response. However, the consequences of GSK3ß inhibition by alternative Ser389 phosphorylation remain poorly characterized. Here we have examined neuroinflammation in GSK3ß Ser389 knock-in (KI) mice, in which the phosphorylation of Ser389 GSK3ß is impaired. The number of activated microglia/infiltrated macrophages, astrocytes, and infiltrated neutrophils was significantly higher in these animals compared to C57BL/6J wild-type (WT) counterparts, which suggests that the failure to inactivate GSK3ß by Ser389 phosphorylation results in sustained low-grade neuroinflammation. Moreover, glial cell activation and brain infiltration of immune cells in response to lipopolysaccharide (LPS) failed in GSK3ß Ser389 KI mice. Such effects were brain-specific, as peripheral immunity was not similarly affected. Additionally, phosphorylation of the IkB kinase complex (IKK) in response to LPS failed in GSK3ß Ser389 KI mice, while STAT3 phosphorylation was fully conserved, suggesting that the NF-κB signaling pathway is specifically affected by this GSK3ß regulatory pathway. Overall, our findings indicate that GSK3ß inactivation by Ser389 phosphorylation controls the brain inflammatory response, raising the need to evaluate its role in the progression of neuroinflammatory pathologies.