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

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 Drp1^ser616. 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.

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