An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation

Area of Science:

• Neuroimmunology
• Endocrinology
• Molecular Biology

Background:

• Microglia and astrocytes are crucial for central nervous system homeostasis.
• Mechanisms regulating inflammatory responses in the CNS are not fully understood.

Purpose of the Study:

• To investigate the role of 5-androsten-3β,17β-diol (ADIOL) in modulating neuroinflammation.
• To elucidate the molecular pathway involving estrogen receptor beta (ERβ) in controlling glial inflammatory responses.

Main Methods:

• Investigated ADIOL's effect on microglia and astrocyte inflammatory responses.
• Analyzed the recruitment of CtBP corepressor complexes to AP-1 promoters.
• Utilized TLR4 agonists and experimental autoimmune encephalomyelitis (EAE) models.
• Examined the impact of reduced ADIOL or ERβ expression.

Main Results:

• ADIOL selectively modulates ERβ to suppress inflammatory responses in microglia and astrocytes.
• ADIOL and specific ERβ ligands recruit CtBP corepressors, repressing inflammatory genes.
• Reduced ADIOL or ERβ leads to exaggerated inflammatory responses.
• ADIOL administration prevents EAE in an ERβ-dependent manner.

Conclusions:

• ADIOL acts via an ERβ/CtBP-transrepression pathway to regulate CNS inflammatory responses.
• This pathway offers a potential therapeutic target for neuroinflammatory conditions.
• Selective ERβ modulators represent a promising strategy for treating neuroinflammation.