GSK3β Inhibition by Phosphorylation at Ser(389) Controls Neuroinflammation

The inhibition of Glycogen Synthase Kinase 3 β (GSK3β) by Ser(9) phosphorylation affects many physiological processes, including the immune response. However, the consequences of GSK3β inhibition by alternative Ser(389) phosphorylation remain poorly characterized. Here we have examined neuroinflammation in GSK3β Ser(389) knock-in (KI) mice, in which the phosphorylation of Ser(389) GSK3β 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 GSK3β by Ser(389) phosphorylation results in sustained low-grade neuroinflammation. Moreover, glial cell activation and brain infiltration of immune cells in response to lipopolysaccharide (LPS) failed in GSK3β Ser(389) 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 GSK3β Ser(389) KI mice, while STAT3 phosphorylation was fully conserved, suggesting that the NF-κB signaling pathway is specifically affected by this GSK3β regulatory pathway. Overall, our findings indicate that GSK3β inactivation by Ser(389) phosphorylation controls the brain inflammatory response, raising the need to evaluate its role in the progression of neuroinflammatory pathologies.