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Updated: Jun 10, 2025
A Preclinical Model of Exertional Heat Stroke in Mice
Published on: July 1, 2021
SIRT1 modulates microglia phenotypes via inhibiting drp1 phosphorylation reduces neuroinflammation in heatstroke
Jie Zhu1, Panshi Jin2, Tingting Zhou3
1Department of Pediatric, Daping Hospital, Army Medical University, China; Department of Pediatric, General Hospital of Southern Theater Command of PLA, Guangzhou 510010, China.
Background:
Brain injury often results in high mortality rates and significant sequelae following severe heatstroke (HS). Neuroinflammation aggravates HS-induced brain injury, yet the involvement of microglia in heat-induced neuroinflammation deserves further investigation.
Methods:
Our study investigated activation status, phenotype markers, production of pro-inflammatory cytokine and reactive oxygen species (ROS) of microglia both in vitro and in vivo under HS. Utilizing high-throughput sequencing, we identified SIRT1 as a potential modulator of microglia phenotype, and observed that SIRT1 alleviated severe heatstroke-induced brain injury following intraperitoneal administration of the SIRT1 agonist SRT-1720 and the inhibitor selisistat. Additionally, the effects of SRT-1720 and selisistat on mitochondrial dynamics and microglial phenotype transition were examined in BV2 cells in vitro.
Results:
Heatstroke promotes microglia activation, as evidenced by the increased production of pro-inflammatory cytokine and reactive oxygen species. High-throughput sequencing revealed elevated expression of SIRT1 in BV2 cells under HS. Upon inhibition of SIRT1 expression, there was a corresponding increase in pro-inflammatory cytokine, iNOS, and ROS expression in BV2 cells. In vivo experiments with the SIRT1 agonist SRT-1720 showed a mitigation of neuron injury under HS, as assessed by Nissl and HE staining. Activation of SIRT1 was associated with a reduction in mitochondrial injury and a decrease in the phosphorylation of mitochondrial fission protein Drp1ser616. Furthermore, the heat-induced activation of microglia was reversed by the Drp1 inhibitor, Mdivi.
Conclusions:
Our findings provided evidence that SIRT1 played a crucial role in inhibiting heat stress-induced microglial activation. By suppressing the phosphorylation of mitochondrial fission protein Drp1, SIRT1 contributed to the reduction of neuroinflammation and severity of heatstroke-induced brain injury.
Insights
Severe heatstroke causes brain injury and neuroinflammation. SIRT1 activation inhibits microglia activation, reducing brain damage by suppressing mitochondrial fission protein Drp1 phosphorylation.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Severe heatstroke (HS) is associated with high mortality and brain injury.
- Neuroinflammation exacerbates HS-induced brain damage.
- The role of microglia in heat-induced neuroinflammation requires further investigation.
Purpose of the Study:
- To investigate microglia activation, phenotype, and inflammatory mediator production under HS conditions.
- To identify potential modulators of microglia phenotype in HS.
- To evaluate the therapeutic potential of targeting SIRT1 in HS-induced brain injury.
Main Methods:
- In vitro and in vivo studies of microglia under HS.
- High-throughput sequencing to identify gene expression changes.
- Assessment of pro-inflammatory cytokines, reactive oxygen species (ROS), and mitochondrial dynamics.
- Administration of SIRT1 agonist (SRT-1720) and inhibitor (selisistat).
Main Results:
- Heatstroke activates microglia, increasing pro-inflammatory cytokines and ROS.
- SIRT1 expression was elevated in microglia under HS.
- SIRT1 inhibition exacerbated inflammatory responses.
- SRT-1720 treatment mitigated brain injury and reduced mitochondrial damage by inhibiting Drp1 phosphorylation.
- Drp1 inhibition reversed heat-induced microglial activation.
Conclusions:
- SIRT1 plays a critical role in suppressing heat stress-induced microglial activation.
- SIRT1 mitigates HS-induced brain injury by reducing neuroinflammation.
- Targeting SIRT1 and mitochondrial dynamics offers a potential therapeutic strategy for heatstroke brain injury.
