Cholesterol-dependent LXR transcription factor activity represses pronociceptive effects of estrogen in sensory neurons and pain induced by myelin basic protein fragments

Background: A bioactive myelin basic protein (MBP) fragment, comprising MBP_84-104, is released in sciatic nerve after chronic constriction injury (CCI). Intraneural injection (IN) of MBP_84-104 in an intact sciatic nerve is sufficient to induce persistent neuropathic pain-like behavior via robust transcriptional remodeling at the injection site and ipsilateral dorsal root ganglia (DRG) and spinal cord. The sex (female)-specific pronociceptive activity of MBP_84-104 associates with sex-specific changes in cholesterol metabolism and activation of estrogen receptor (ESR)1 signaling. Methods: In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP_84-104 interactors by mass spectrometry of MBP_84-104 pull-down; and (iii) liver X receptor (LXR)α protein expression by immunoblotting. To test the effect of LXRα stimulation on IN MBP_84-104-induced mechanical hypersensitivity, the LXRα expression was confirmed along the segmental neuraxis, in DRG and spinal cord, followed by von Frey testing of the effect of intrathecally administered synthetic LXR agonist, GW3965. In cultured male and female rat DRGs exposed to MBP_84-104 and/or estrogen treatments, transcriptional effect of LXR stimulation by GW3965 was assessed on downstream cholesterol transporter Abc, interleukin (IL)-6, and pronociceptive Cacna2d1 gene expression. Results: CCI regulated LXRα ligand and receptor levels in nerves of both sexes, with cholesterol precursors, desmosterol and 7-DHC, and oxysterol elevated in females relative to males. MBP_84-104 interacted with nuclear receptor coactivator (Ncoa)1, known to activate LXRα, injury-specific in nerves of both sexes. LXR stimulation suppressed ESR1-induced IL-6 and Cacna2d1 expression in cultured DRGs of both sexes and attenuated MBP_84-104-induced pain in females. Conclusion: The injury-released bioactive MBP fragments induce pronociceptive changes by selective inactivation of nuclear transcription factors, including LXRα. By Ncoa1 sequestration, bioactive MBP fragments render LXRα function to counteract pronociceptive activity of estrogen/ESR1 in sensory neurons. This effect of MBP fragments is prevalent in females due to high circulating estrogen levels in females relative to males. Restoring LXR activity presents a promising therapeutic strategy in management of neuropathic pain induced by bioactive MBP.