Journal
NEURON
Volume 93, Issue 3, Pages 574-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2016.12.021
Keywords
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Categories
Funding
- NIH (New Innovator Award) [DP2 NS083038]
- NIH (EUREKA Award) [R01 NS085938]
- NIH [P30 CA014195, P30 NS072031, R01 AI101400, R01 NS085296]
- Rita Allen Foundation
- Whitehall Foundation
- Brain Research Foundation
- Waitt Foundation
- Hearst Foundation
- Richard Allan Barry Family Foundation
- Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]
- Nomis Foundation
- H.N. and Frances C. Berger Foundation
- Fritz B. Burns Foundation
- HKT Foundation
- NCI [P30 CA014195, R01 CA137094-06]
- William Scandling Trust
- Price Family Foundation
- Marshall Legacy Foundation
- Pioneer Fund postdoctoral scholar award
- Catharina Foundation postdoctoral scholar award
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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.
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