HDAC7 Activates IKK/NF-κB Signaling to Regulate Astrocyte-Mediated Inflammation

Class IIa histone deacetylases (HDAC) have been shown to drive innate immune cell-mediated inflammation in the peripheral system, but their roles in cerebral inflammatory responses remain largely unknown. Here, we elucidate that HDAC7 is selectively elevated in lipopolysaccharide (LPS)-challenged astrocytes both in vivo and in vitro. We identify that HDAC7 binds to the inhibitory kappa B kinase (IKK) to promote IKK alpha and IKK beta deacetylation and subsequent activation, leading to the activation of nuclear factor kappa B (NF-kappa B). Astrocyte-specific overexpression of HDAC7 results in NF-kappa B activation, pro-inflammatory gene upregulation and anxiety-like behaviors in mice, while downregulating HDAC7 reserves LPS-induced NF-kappa B activation and inflammatory responses. Furthermore, pharmacological inhibition of HDAC7 by a class IIa HDAC inhibitor attenuates LPS -induced NF-kappa B activation, inflammatory responses and anxiety-like behaviors both in vivo and in vitro. Together, our data reveal a novel mechanism of HDAC7 in astrocyte-mediated inflammation and suggest that targeting HDAC7 could be a potential therapeutic strategy for the treatment of anxiety and other inflammation-related diseases.

Automated summary

Class IIa histone deacetylases (HDAC) play a role in inflammation by promoting IKK activation and subsequent NF-kappa B activation. In this study, HDAC7 was found to be elevated in astrocytes after LPS challenge, leading to NF-kappa B activation, pro-inflammatory gene upregulation, and anxiety-like behaviors. Inhibition of HDAC7 attenuated LPS-induced inflammation and anxiety-like behaviors.