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Phosphatidylserine Exposure Controls Viral Innate Immune Responses by Microglia
Yusuf Tufail1, Daniela Cook1, Lawrence Fourgeaud2
1Waitt Advanced Biophotonics Center, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Abstract:
Microglia are the intrinsic immune sentinels of the central nervous system. Their activation restricts tissue injury and pathogen spread, but in some settings, including viral infection, this response can contribute to cell death and disease. Identifying mechanisms that control microglial responses is therefore an important objective. Using replication-incompetent adenovirus 5 (Ad5)-based vectors as a model, we investigated the mechanisms through which microglia recognize and respond to viral uptake. Transgenic, immunohistochemical, molecular-genetic, and fluorescence imaging approaches revealed that phosphatidylserine (PtdSer) exposure on the outer leaflet of transduced cells triggers their engulfment by microglia through TAM receptor-dependent mechanisms. We show that inhibition of phospholipid scramblase 1 (PLSCR1) activity reduces intracellular calcium dysregulation, prevents PtdSer externalization, and enables months-long protection of vector-transduced, transgene-expressing cells from microglial phagocytosis. Our study identifies PLSCR1 as a potent target through which the innate immune response to viral vectors, and potentially other stimuli, may be controlled.
Insights
Microglia recognize virus-transduced cells via phosphatidylserine (PtdSer) exposure. Inhibiting phospholipid scramblase 1 (PLSCR1) prevents this, protecting cells from microglial engulfment and potential damage.
Area of Science:
- Neuroimmunology
- Cellular Biology
- Virology
Background:
- Microglia are the central nervous system's immune cells.
- While protective, microglial activation can cause cell death during viral infections.
- Controlling microglial responses is crucial for managing neuroinflammation.
Purpose of the Study:
- To investigate how microglia recognize and respond to virus-transduced cells.
- To identify molecular mechanisms governing microglial phagocytosis of infected cells.
Main Methods:
- Utilized adenovirus 5 (Ad5)-based vectors as a model system.
- Employed transgenic, immunohistochemical, molecular-genetic, and fluorescence imaging techniques.
- Assessed the role of phosphatidylserine (PtdSer) exposure and phospholipid scramblase 1 (PLSCR1).
Main Results:
- Phosphatidylserine (PtdSer) exposure on transduced cells signals microglia for engulfment via TAM receptors.
- Inhibition of phospholipid scramblase 1 (PLSCR1) activity prevents PtdSer externalization and calcium dysregulation.
- Blocking PLSCR1 provided long-term protection of vector-transduced cells from microglial phagocytosis.
Conclusions:
- Identified PLSCR1 as a key regulator of microglial phagocytosis in response to viral vectors.
- PLSCR1 inhibition offers a potential strategy to control innate immune responses and mitigate cell death.
- Findings have implications for managing viral infections and gene therapy vector safety.
