Attenuation of neuronal ferroptosis in intracerebral hemorrhage by inhibiting HDAC1/2: Microglial heterogenization via the Nrf2/HO1 pathway.
CNS Neurosci Ther
; 30(3): e14646, 2024 03.
Article
en En
| MEDLINE
| ID: mdl-38523117
ABSTRACT
AIM:
The class I histone deacetylases (HDACs) implicate in microglial heterogenization and neuroinflammation following Intracerebral hemorrhage (ICH). Ferroptosis has also been reported in the ICH model. However, the relationship between HDAC1/2's role in microglial heterogenization and neuronal ferroptosis remains unclear.METHODS:
In both in vivo and in vitro models of ICH, we used Romidepsin (FK228), a selective HDAC1/2 inhibitor, to investigate its effects on microglial heterogenization and neuronal ferroptosis. In the in vitro ICH model using Hemin, a transwell system was utilized to examine how microglia-driven inflammation and ICH-triggered neuronal ferroptosis interact. Immunostaining, Western blotting and RT-qPCR were used to evaluate the microglial heterogenization and neuronal ferroptosis. Microglial heterogenization, neuronal ferroptosis, and neurological dysfunctions were assessed in vivo ICH mice model performed by autologous blood injection.RESULTS:
HDAC1/2 inhibition altered microglial heterogenization after ICH, as showing the reducing neuroinflammation and shifting microglia towards an anti-inflammatory phenotype by immunostaining and qPCR results. HDAC1/2 inhibition reduced ferroptosis, characterized by high ROS and low GPx4 expression in HT22 cells, and reduced iron and lipid deposition post-ICH in vivo. Additionally, the Nrf2/HO1 signaling pathway, especially acetyl-Nrf2, activated in the in vivo ICH model due to HDAC1/2 inhibition, plays a role in regulating microglial heterogenization. Furthermore, HDAC1/2 inhibition improved sensorimotor and histological outcomes post-ICH, offering a potential mechanism against ICH.CONCLUSION:
Inhibition of HDAC1/2 reduces neuro-ferroptosis by modifying the heterogeneity of microglia via the Nrf2/HO1 pathway, with a particular focus on acetyl-Nrf2. Additionally, this inhibition aids in the faster removal of hematomas and lessens prolonged neurological impairments, indicating novel approach for treating ICH.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Microglía
/
Ferroptosis
Límite:
Animals
Idioma:
En
Revista:
CNS Neurosci Ther
Asunto de la revista:
NEUROLOGIA
/
TERAPEUTICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Reino Unido