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DHEA Attenuates Microglial Activation via Induction of JMJD3 in Experimental Subarachnoid Haemorrhage
Tao Tao1, Guang-Jie Liu2, Xuan Shi3
1Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, Jiangsu, China.
Background:
Microglia are resident immune cells in the central nervous system and central to the innate immune system. Excessive activation of microglia after subarachnoid haemorrhage (SAH) contributes greatly to early brain injury, which is responsible for poor outcomes. Dehydroepiandrosterone (DHEA), a steroid hormone enriched in the brain, has recently been found to regulate microglial activation. The purpose of this study was to address the role of DHEA in SAH.
Methods:
We used in vivo models of endovascular perforation and in vitro models of haemoglobin exposure to illustrate the effects of DHEA on microglia in SAH.
Results:
In experimental SAH mice, exogenous DHEA administration increased DHEA levels in the brain and modulated microglial activation. Ameliorated neuronal damage and improved neurological outcomes were also observed in the SAH mice pretreated with DHEA, suggesting neuronal protective effects of DHEA. In cultured microglia, DHEA elevated the mRNA and protein levels of Jumonji d3 (JMJD3, histone 3 demethylase) after haemoglobin exposure, downregulated the H3K27me3 level, and inhibited the transcription of proinflammatory genes. The devastating proinflammatory microglia-mediated effects on primary neurons were also attenuated by DHEA; however, specific inhibition of JMJD3 abolished the protective effects of DHEA. We next verified that DHEA-induced JMJD3 expression, at least in part, through the tropomyosin-related kinase A (TrkA)/Akt signalling pathway.
Conclusions:
DHEA has a neuroprotective effect after SAH. Moreover, DHEA increases microglial JMJD3 expression to regulate proinflammatory/anti-inflammatory microglial activation after haemoglobin exposure, thereby suppressing inflammation.
Insights
Dehydroepiandrosterone (DHEA) protects the brain after subarachnoid hemorrhage (SAH) by regulating microglial activation. DHEA enhances microglial JMJD3 expression, suppressing inflammation and improving neurological outcomes in SAH models.
Area of Science:
- Neuroscience
- Immunology
- Endocrinology
Background:
- Microglia, the brain's immune cells, become excessively activated after subarachnoid hemorrhage (SAH), contributing to early brain injury.
- Dehydroepiandrosterone (DHEA), a brain-enriched steroid hormone, modulates microglial activation.
Purpose of the Study:
- To investigate the role of DHEA in the context of SAH.
Main Methods:
- Utilized in vivo (endovascular perforation) and in vitro (hemoglobin exposure) models to study DHEA's effects on microglia in SAH.
- Assessed microglial activation, neuronal damage, neurological outcomes, and gene/protein expression (JMJD3, H3K27me3).
Main Results:
- Exogenous DHEA administration in SAH mice increased brain DHEA levels, modulated microglial activation, reduced neuronal damage, and improved neurological function.
- In cultured microglia, DHEA increased JMJD3 expression, decreased H3K27me3 levels, and inhibited pro-inflammatory gene transcription.
- DHEA's protective effects were dependent on JMJD3 expression, mediated partly via the TrkA/Akt signaling pathway.
Conclusions:
- DHEA exhibits neuroprotective effects following SAH.
- DHEA enhances microglial JMJD3 expression, regulating pro-inflammatory and anti-inflammatory microglial responses to hemoglobin exposure and suppressing inflammation.
