Dysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation

Microglia are integral mediators of innate immunity within the mammalian central nervous system. Typical microglial responses are transient, intending to restore homeostasis by orchestrating the removal of pathogens and debris and the regeneration of damaged neurons. However, prolonged and persistent microglial activation can drive chronic neuroinflammation and is associated with neurodegenerative disease. Recent evidence has revealed that abnormalities in microglial signaling pathways involving phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) may contribute to altered microglial activity and exacerbated neuroimmune responses. In this scoping review, the known and suspected roles of PI3K-AKT signaling in microglia, both during health and pathological states, will be examined, and the key microglial receptors that induce PI3K-AKT signaling in microglia will be described. Since aberrant signaling is correlated with neurodegenerative disease onset, the relationship between maladapted PI3K-AKT signaling and the development of neurodegenerative disease will also be explored. Finally, studies in which microglial PI3K-AKT signaling has been modulated will be highlighted, as this may prove to be a promising therapeutic approach for the future treatment of a range of neuroinflammatory conditions.