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Dysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation
Erskine Chu1,2, Richelle Mychasiuk2,3, Margaret L Hibbs4
1Department of Immunology and Pathology, Central Clinical School, Monash University, Level 6, 89 Commercial Road, Melbourne, VIC, 3004, Australia.
Abstract:
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.
Insights
Dysregulated phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling in microglia contributes to neuroinflammation and neurodegenerative diseases. Modulating this pathway offers potential therapeutic strategies for these conditions.
Area of Science:
- Neuroimmunology
- Cellular Signaling
- Neurodegenerative Diseases
Background:
- Microglia are key innate immune cells in the central nervous system, crucial for maintaining homeostasis.
- Persistent microglial activation drives chronic neuroinflammation, a hallmark of neurodegenerative diseases.
- Aberrant phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling pathways are implicated in altered microglial function.
Purpose of the Study:
- To review the roles of PI3K-AKT signaling in microglia during both healthy and pathological conditions.
- To identify microglial receptors that initiate PI3K-AKT signaling.
- To explore the link between maladapted PI3K-AKT signaling and neurodegeneration.
Main Methods:
- Scoping review methodology.
- Examination of existing literature on microglial PI3K-AKT signaling.
- Analysis of studies involving modulation of microglial PI3K-AKT signaling.
Main Results:
- PI3K-AKT signaling pathways are critical in regulating microglial responses.
- Abnormalities in this signaling cascade are associated with neuroinflammation and neurodegenerative disease progression.
- Specific microglial receptors trigger PI3K-AKT activation.
Conclusions:
- Maladaptive PI3K-AKT signaling in microglia is a significant factor in neurodegenerative disease development.
- Targeting microglial PI3K-AKT signaling presents a promising therapeutic avenue for neuroinflammatory disorders.
- Further research into modulating this pathway could lead to novel treatments.
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