SIRT1 modulates microglia phenotypes via inhibiting drp1 phosphorylation reduces neuroinflammation in heatstroke

  • Brain Res Bull. 2024 Nov:218:111101. doi: 10.1016/j.brainresbull.2024.111101.
Jie Zhu  1 ,  Panshi Jin  2 ,  Tingting Zhou  3 ,  Dingshun Zhang  4 ,  Zixin Wang  5 ,  Zhen Tang  3 ,  Zhifeng Liu  6 ,  Guangli Ren  7
Affiliations
  • 1. Department of Pediatric, Daping Hospital, Army Medical University, China; Department of Pediatric, General Hospital of Southern Theater Command of PLA, Guangzhou 510010, China. Electronic address: [email protected].
  • 2. Department of Plastic Surgery, General Hospital of Southern Theater Command of PLA, Guangzhou 510010, China.
  • 3. Department of Pediatric, General Hospital of Southern Theater Command of PLA, Guangzhou 510010, China.
  • 4. Department of Medicine Intensive Care Unit, General Hospital of Southern Theater Command of PLA, Guangzhou 510010, China.
  • 5. Department of Metabolic Surgery, Jinshazhou Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510010, China.
  • 6. Department of Medicine Intensive Care Unit, General Hospital of Southern Theater Command of PLA, Guangzhou 510010, China; Southern Medical University, Guangzhou 510010, China. Electronic address: [email protected].
  • 7. Department of Pediatric, General Hospital of Southern Theater Command of PLA, Guangzhou 510010, China; Southern Medical University, Guangzhou 510010, China. Electronic address: [email protected].
PMID: 39396713 DOI: 10.1016/j.brainresbull.2024.111101
Abstract

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.

Keywords
Heatstroke; Microglia; Mitochondrial quality control; Neuroinflammation; SIRT1.
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