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P2Y12 expression and function in alternatively activated human microglia
Craig S Moore1, Ariel R Ase1, Angham Kinsara1
1Division of BioMedical Sciences (C.S.M.), Neuroscience, Memorial University of Newfoundland and Labrador, St. John's, Newfoundland, Canada; Neuroimmunology Unit (C.S.M., A.A., A.K., V.T.S.R., M.M.-R., S.Y.L., P.S., A.B.-O., J.P.A.), Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada; Center for Neurologic Diseases (O.B.), Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and Department of Pathology and Molecular Medicine (S.K.L.), Queens University, Kingston, Ontario, Canada.
Objective:
To investigate and measure the functional significance of altered P2Y12 expression in the context of human microglia activation.
Methods:
We performed in vitro and in situ experiments to measure how P2Y12 expression can influence disease-relevant functional properties of classically activated (M1) and alternatively activated (M2) human microglia in the inflamed brain.
Results:
We demonstrated that compared to resting and classically activated (M1) human microglia, P2Y12 expression is increased under alternatively activated (M2) conditions. In response to ADP, the endogenous ligand of P2Y12, M2 microglia have increased ligand-mediated calcium responses, which are blocked by selective P2Y12 antagonism. P2Y12 antagonism was also shown to decrease migratory and inflammatory responses in human microglia upon exposure to nucleotides that are released during CNS injury; no effects were observed in human monocytes or macrophages. In situ experiments confirm that P2Y12 is selectively expressed on human microglia and elevated under neuropathologic conditions that promote Th2 responses, such as parasitic CNS infection.
Conclusion:
These findings provide insight into the roles of M2 microglia in the context of neuroinflammation and suggest a mechanism to selectively target a functionally unique population of myeloid cells in the CNS.
Insights
P2Y12 expression is elevated in alternatively activated (M2) human microglia, influencing their calcium responses and migration. Blocking P2Y12 offers a targeted approach for neuroinflammation treatment.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia play crucial roles in brain immunity and neuroinflammation.
- P2Y12 receptor is expressed on myeloid cells, but its specific role in human microglia subtypes is not fully understood.
Purpose of the Study:
- To investigate the functional significance of P2Y12 receptor expression in human microglia activation.
- To determine how P2Y12 influences the properties of M1 and M2 microglia in the inflamed brain.
Main Methods:
- In vitro and in situ experiments were conducted on human microglia.
- P2Y12 expression and function were assessed in resting, M1, and M2 microglia.
- Functional assays included calcium responses, migration, and inflammatory marker analysis.
Main Results:
- P2Y12 expression is significantly increased in alternatively activated (M2) human microglia compared to resting and M1 states.
- M2 microglia exhibit enhanced ADP-mediated calcium responses via P2Y12, which are blocked by antagonism.
- P2Y12 antagonism reduced migration and inflammatory responses in human microglia exposed to CNS injury-related nucleotides.
- P2Y12 was selectively expressed on human microglia and elevated in neuropathologic conditions associated with Th2 responses.
Conclusions:
- P2Y12 is selectively upregulated on M2 microglia and contributes to their functional properties.
- Targeting P2Y12 offers a potential strategy for modulating M2 microglia in neuroinflammatory diseases.
- These findings provide insights into the specific roles of M2 microglia in neuroinflammation and suggest a mechanism for selective myeloid cell targeting in the CNS.
