Cell Reports
Volume 27, Issue 10, 4 June 2019, Pages 2895-2908.e4
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Article
Nanoscale Surveillance of the Brain by Microglia via cAMP-Regulated Filopodia

https://doi.org/10.1016/j.celrep.2019.05.010Get rights and content
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Highlights

  • Microglia use actin-dependent filopodia to efficiently sample the brain parenchyma

  • Intracellular cAMP drives filopodia growth but induces large process retraction

  • Norepinephrine and nitric oxide contribute to cAMP-driven filopodia extension

  • Fine filopodia and large processes establish dual-scale surveillance by microglia

Summary

Microglia, the brain’s immune cells, maintain homeostasis and sense pathological changes by continuously surveying the parenchyma with highly motile large processes. Here, we demonstrate that microglia also use thin actin-dependent filopodia that allow fast nanoscale sensing within discrete regions. Filopodia are distinct from large processes by their size, speed, and regulation mechanism. Increasing cyclic AMP (cAMP) by activating norepinephrine Gs-coupled receptors, applying nitric oxide, or inhibiting phosphodiesterases rapidly increases filopodia but collapses large processes. Alternatively, Gi-coupled P2Y12 receptor activation collapses filopodia but triggers large processes extension with bulbous tips. Similar control of cytoskeletal dynamics and microglial morphology by cAMP is observed in ramified primary microglia, suggesting that filopodia are intrinsically generated sensing structures. Therefore, nanoscale surveillance of brain parenchyma by microglia requires localized cAMP increases that drive filopodia formation. Shifting intracellular cAMP levels controls the polarity of microglial responses to changes in brain homeostasis and alters the scale of immunosurveillance.

Keywords

microglia
immune surveillance
filopodia
cyclic AMP
THIK-1
actin
cytoskeletal dynamics
norepinephrine
nitric oxide
phosphodiesterase

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