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Roles for innate immunity in neurological and psychiatric disorders

開催日 2014/9/12
時間 17:10 - 19:10
会場 Room E(301)
Chairperson(s) 山中 宏二 / Koji Yamanaka (名古屋大学環境医学研究所病態神経科学分野 / Research Institute of Environmental Medicine, Nagoya University, Japan)
古屋敷 智之 / Tomoyuki Furuyashiki (神戸大学大学院医学研究科薬理学 / Division of Pharmacology, Kobe University Graduate School of Medicine, Japan)

Nuclear receptor-mediated regulation of innate immune responses in microglia cells and their impact on neurological disease

  • S2-E-3-3
  • Kaoru Saijo:1 
  • 1:University of California, Berkeley, USA 

Microglia and astrocytes play essential roles in the maintenance of homeostasis within the central nervous system (CNS). However, the mechanisms that control the magnitude and duration of responses to infection and injury, as well as how inflammation is resolved, remain poorly understood. Recently, we found evidence that 5-androsten-3β,17β-diol (Δ5-ADIOL) functions as a selective modulator of estrogen receptor β (ERβ) to suppress the inflammatory responses of microglia. Δ5-ADIOL and a subset of synthetic ERβ-specific ligands, but not 17β-estradiol, mediate recruitment of CtBP co-repressor complexes to AP-1-dependent gene promoters, thereby repressing specific subsets of genes that amplify inflammatory responses in microglia and astrocytes. Δ5-ADIOL is converted from its precursor, 5-androsten-3β-ol-17-one (DHEA), by the enzymatic activity of the 17β-hydroxysteroid dehydrogenase (17β-HSD) family of proteins. We also found that inflammatory stimuli, such as LPS, down-regulate the mRNA expressions of most 17β-HSDs, including 17β-HSD type 14 which performs a major role in converting DHEA to Δ5-ADIOL in microglial cells. As a consequence, Δ5-ADIOL secretion by microglia is down-regulated during inflammation. Interestingly, interleukin-10 (IL-10), a major anti-inflammatory cytokine, up-regulates the expression of 17β-HSD type 14, which may restore Δ5-ADIOL levels and reset the ERβ/CtBP repressor complex on target gene promoters. Through the analysis of patients with HIV-associated neurocognitive disorders, we find that those with cognitive impairment exhibit significantly decreased Δ5-ADIOL in their cerebral spinal fluid (CSF) and plasma. Thus, Δ5-ADIOL levels in the CSF might correlate with the patient's status of inflammation and cognition in the CNS.

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