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Updated: Apr 30, 2026
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Systemic inflammation regulates microglial responses to tissue damage in vivo
Stefka Gyoneva1, Dimitrios Davalos, Dipankar Biswas
1Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia.
Abstract:
Microglia, the resident immune cells of the central nervous system, exist in either a "resting" state associated with physiological tissue surveillance or an "activated" state in neuroinflammation. We recently showed that ATP is the primary chemoattractor to tissue damage in vivo and elicits opposite effects on the motility of activated microglia in vitro through activation of adenosine A2A receptors. However, whether systemic inflammation affects microglial responses to tissue damage in vivo remains largely unknown. Using in vivo two-photon imaging of mice, we show that injection of lipopolysaccharide (LPS) at levels that can produce both clear neuroinflammation and some features of sepsis significantly reduced the rate of microglial response to laser-induced ablation injury in vivo. Under proinflammatory conditions, microglial processes initially retracted from the ablation site, but subsequently moved toward and engulfed the damaged area. Analyzing the process dynamics in 3D cultures of primary microglia indicated that only A2A , but not A1 or A3 receptors, mediate process retraction in LPS-activated microglia. The A2A receptor antagonists caffeine and preladenant reduced adenosine-mediated process retraction in activated microglia in vitro. Finally, administration of preladenant before induction of laser ablation in vivo accelerated the microglial response to injury following systemic inflammation. The regulation of rapid microglial responses to sites of injury by A2A receptors could have implications for their ability to respond to the neuronal death occurring under conditions of neuroinflammation in neurodegenerative disorders.
Insights
Systemic inflammation impairs microglial response to injury. Adenosine A2A receptor antagonists restore microglial motility, crucial for neurodegenerative disease research.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the brain's immune cells, shift between resting and activated states.
- ATP is a key chemoattractant to tissue damage, with adenosine A2A receptors mediating opposing effects on microglial motility.
- The impact of systemic inflammation on microglial responses to in vivo tissue damage is largely unknown.
Purpose of the Study:
- To investigate how systemic inflammation affects microglial responses to laser-induced tissue damage in vivo.
- To determine the role of adenosine receptors in modulating microglial behavior under inflammatory conditions.
- To explore therapeutic potential of A2A receptor antagonists in enhancing microglial repair mechanisms.
Main Methods:
- In vivo two-photon imaging in mice to observe microglial dynamics following laser ablation.
- 3D primary microglia cultures to analyze receptor-mediated process retraction.
- Pharmacological manipulation using A2A receptor antagonists (caffeine, preladenant).
Main Results:
- Lipopolysaccharide (LPS) induced systemic inflammation significantly slowed microglial response to ablation injury.
- Activated microglia exhibited initial process retraction followed by engulfment of damaged tissue.
- Adenosine A2A receptors were identified as key mediators of process retraction in LPS-activated microglia.
- A2A receptor antagonists (caffeine, preladenant) reversed adenosine-mediated retraction in vitro and accelerated in vivo microglial response post-LPS.
Conclusions:
- Systemic inflammation, induced by LPS, impairs the rapid recruitment of microglia to sites of injury.
- Adenosine A2A receptor signaling plays a critical role in regulating microglial process dynamics during inflammation.
- Targeting A2A receptors with antagonists can restore and enhance microglial responsiveness to injury in inflammatory states.
- These findings have implications for understanding and treating neurodegenerative disorders characterized by neuroinflammation.
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