Epigenetic suppression of liver X receptor ? in anterior cingulate cortex by HDAC5 drives CFA-induced chronic inflammatory pain.

ABSTRACT: BACKGROUND:Liver X receptors (LXRs), including LXR? and LXR?, are key regulators of transcriptional programs for both cholesterol homeostasis and inflammation in the brain. Here, the modes of action of LXRs and the epigenetic mechanisms regulating LXR? expression in anterior cingulate cortex (ACC) of chronic inflammatory pain (CIP) are investigated. METHODS:The deficit of LXR isoform and analgesic effect of LXR activation by GW3965 were evaluated using the mouse model of CIP induced by hindpaw injection of complete Freund's adjuvant (CFA). The mechanisms involved in GW-mediated analgesic effects were analyzed with immunohistochemical methods, ELISA, co-immunoprecipitation (Co-IP), Western blot, and electrophysiological recording. The epigenetic regulation of LXR? expression was investigated by chromatin immunoprecipitation, quantitative real-time PCR, and sequencing. RESULTS:We revealed that CFA insult led to LXR? reduction in ACC, which was associated with upregulated expression of histone deacetylase 5 (HDAC5), and knockdown of LXR? by shRNA led to thermal hyperalgesia. Co-IP showed that LXR? interacted with NF-?B p65 physically. LXR? activation by GW3965 exerted analgesic effects by inhibiting the nuclear translocation of NF-?B, reducing the phosphorylation of mitogen-activated protein kinases (MAPKs) in ACC, and decreasing the promoted input-output and enhanced mEPSC frequency in ACC neurons after CFA exposure. In vitro experiments confirmed that HDAC5 triggered histone deacetylation on the promoter region of Lxr?, resulting in downregulation of Lxr? transcription. CONCLUSION:These findings highlight an epigenetic mechanism underlying LXR? deficits linked to CIP, and LXR? activation may represent a potential novel target for the treatment of CIP with an alteration in inflammation responses and synaptic transmission in ACC.

SUBMITTER: Li YJ 

PROVIDER: S-EPMC6599528 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature