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Updated: May 28, 2026
Two-photon Imaging of Microglial Processes' Attraction Toward ATP or Serotonin in Acute Brain Slices
Published on: January 31, 2019
Temperature-related effects of adenosine triphosphate-activated microglia on pro-inflammatory factors
Tomohiro Matsui1, Yukari Motoki, Takafumi Inomoto
1Department of Laboratory Sciences, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan. giants@yamaguchi-u.ac.jp
Background:
Therapeutic hypothermia protects neurons after severe brain injury. Activated microglia produce several neurotoxic factors, such as pro-inflammatory cytokines and nitric oxide (NO), during neuron destruction. Hence, suppression of microglial release of these factors is thought to contribute partly to the neuroprotective effects of hypothermia. After brain insults, adenosine triphosphate (ATP) is released from injured cells and activates microglia. Here, we examined the acute effects of temperature on ATP-activated microglial production of inflammatory factors, and the possible involvement of p38 mitogen-activated protein kinase (p38) underlying such effects.
Methods:
Microglia were cultured with ATP at 33, 37, and 39°C, or with ATP in the presence of a p38 inhibitor, SB203580, at 37°C. Cytokine and NO levels, and p38 activation were measured.
Results:
Compared to 37°C, TNF-α was reduced at 33°C and augmented at 39°C for 1.5 h. IL-6 was reduced at 33°C for 6 h. NO was reduced at 33°C, but augmented at 39°C for 6 h. p38 was reduced at 33°C for 1 min. SB203580 inhibited ATP-induced TNF-α, IL-6, and NO production.
Conclusion:
Lowering temperature rapidly reduced p38 activation and the subsequent p38-regulated production of pro-inflammatory cytokines and NO in ATP-activated microglia, suggesting that attenuation of early phase inflammatory responses via suppression of p38 in microglia is one possible neuroprotective mechanism of therapeutic hypothermia. Temperature elevation increased TNF-α and NO production in these cells. These temperature-dependent changes imply that monitoring of TNF-α and NO in the cerebrospinal fluid during the early phase might be useful as biomarkers for responses to therapeutic hypothermia and hyperthermia.
Insights
Therapeutic hypothermia reduces microglial inflammatory factor release by inhibiting p38 activation. Lowering temperature offers neuroprotection by suppressing early inflammatory responses, while higher temperatures increase these factors.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Therapeutic hypothermia aids neuroprotection after brain injury.
- Activated microglia release neurotoxic factors like cytokines and nitric oxide (NO).
- Adenosine triphosphate (ATP) released from injured cells activates microglia.
Purpose of the Study:
- To investigate the acute effects of temperature on ATP-activated microglial inflammatory factor production.
- To explore the role of p38 mitogen-activated protein kinase (p38) in temperature-dependent microglial activation.
Main Methods:
- Microglia were cultured with ATP at varying temperatures (33°C, 37°C, 39°C).
- The effect of a p38 inhibitor (SB203580) on microglial activation at 37°C was assessed.
- Levels of TNF-α, IL-6, NO, and p38 activation were measured.
Main Results:
- Lower temperatures (33°C) reduced TNF-α, IL-6, NO, and p38 activation compared to 37°C.
- Higher temperatures (39°C) increased TNF-α and NO production.
- p38 inhibition suppressed ATP-induced TNF-α, IL-6, and NO release.
Conclusions:
- Reduced p38 activation at lower temperatures attenuates early inflammatory responses, contributing to hypothermia's neuroprotective effects.
- Temperature elevation enhances TNF-α and NO production in microglia.
- Monitoring TNF-α and NO may serve as biomarkers for therapeutic hypothermia and hyperthermia responses.
