Regulator of G‐protein Signaling 10 (RGS10) Expression is Transcriptionally Silenced in Activated Microglia by Histone Deacetylase Activity

Abstract

Regulator of G‐protein Signaling 10 (RGS10) has emerged as a key regulator of pro‐inflammatory cytokine production in microglia, functioning as an important neuroprotective factor. While RGS10 is normally expressed in microglia at high levels, expression is silenced in vitro following activation of TLR4 receptor‐activation. Given the ability of RGS10 to regulate inflammatory signaling, dynamic regulation of RGS10 expression in microglia may be an important mechanism to tune inflammatory responses. The goals of the current study were to confirm that RGS10 is silenced in an in vivo inflammatory model of microglial activation and to determine the mechanism for activation‐dependent silencing of RGS10 expression in microglia. We demonstrate that RGS10 is endogenously expressed in spinal cord microglia, and expression is suppressed in the spinal cord in a nerve injury induced neuropathic pain mouse model. We show that the histone deacetylase (HDAC) enzyme inhibitor Trichostatin A blocks the ability of Lipopolysaccharide (LPS) to suppress RGS10 transcription in BV‐2 and primary microglia, demonstrating that HDAC enzymes are required for LPS silencing of RGS10. Further, we used chromatin immunoprecipitation to demonstrate that H3 histones at the RGS10 proximal promoter are deacetylated in BV‐2 microglia following LPS activation, and HDAC1 association at the RGS10 promoter is enhanced following LPS stimulation. Finally, we have shown that sphingosine 1‐phosphate, an endogenous microglial signaling mediator which inhibits HDAC activity, enhances basal RGS10 expression in BV‐2 microglia, suggesting that RGS10 expression is dynamically regulated in microglia in response to multiple signals.Support or Funding InformationThis work was supported by grants from the National Multiple Sclerosis Society (SBH) and the National Institutes of Neurological Disorders and Stroke [RO1NS064289] (HRW).