A myelin basic protein fragment induces sexually dimorphic transcriptome signatures of neuropathic pain in mice

Abstract

In the peripheral nerve, mechanosensitive axons are insulated by myelin, a multilamellar membrane formed by Schwann cells. Here, we offer first evidence that a myelin degradation product induces mechanical hypersensitivity and global transcriptomics changes in a sex-specific manner. Focusing on downstream signaling events of the functionally active 84-104 myelin basic protein (MBP84-104) fragment released after nerve injury, we demonstrate that exposing the sciatic nerve to MBP84-104 via endoneurial injection produces robust mechanical hypersensitivity in female, but not in male, mice. RNA-Seq and systems biology analyses revealed a striking sexual dimorphism in molecular signatures of the dorsal root ganglia (DRG) and spinal cord response, not observed at the nerve injection site. Mechanistically, intra-sciatic MBP84-104 induced phospholipase C (PLC)-driven (females) and phosphoinositide 3-kinase-driven (males) phospholipid metabolism (tier 1). PLC/inositol trisphosphate receptor (IP3R) and estrogen receptor co-regulation in spinal cord yielded Ca2+-dependent nociceptive signaling induction in females that was suppressed in males (tier 2). IP3R inactivation by intrathecal xestospongin C attenuated the female-specific hypersensitivity induced by MBP84-104. According to sustained sensitization in tiers 1–2, T cell–related signaling spreads to the DRG and spinal cord in females, but remains localized to the sciatic nerve in males (tier 3). These results are consistent with our previous finding that MBP84-104–induced pain is T cell–dependent. In summary, an autoantigenic peptide endogenously released in nerve injury triggers multi-site, sex-specific transcriptome changes, leading to neuropathic pain only in female mice. MBP84-104 acts through sustained co-activation of metabolic, estrogen receptor–mediated nociceptive and autoimmune signaling programs.

B cell Activity and anti-MBP Autoantibody Response to Peripheral Nerve Injury is Sexually Dimorphic

“…The released dMBP/MBP(69-86) peptide levels and the MBP-degrading protease activity [55] are comparable in female and male CCI nerves, suggesting that sexual dimorphism arises downstream of the MBP epitope action [43]. The equal-dose intraneural MBP(84-104) induces female-speci c mechanical hypersensitivity through a vast and sex-speci c transcriptional reprogramming in the nerves and the corresponding DRG and spinal cord [43]. Among the major multi-systemic changes induced by intraneural MBP(84-104) is sex-speci c changes in lipid-calcium metabolism, T and B cell-related gene activity progressing from the nerve to DRG and spinal cord only in females, but not males [43].…”

“…The released dMBP/MBP(69-86) peptide levels and the MBP-degrading protease activity [55] are comparable in female and male CCI nerves, suggesting that sexual dimorphism arises downstream of the MBP epitope action [43]. The equal-dose intraneural MBP(84-104) induces female-speci c mechanical hypersensitivity through a vast and sex-speci c transcriptional reprogramming in the nerves and the corresponding DRG and spinal cord [43].…”

“…To assess the serum levels of IgM and IgG anti-MBP autoantibody in female and male rats post-CCI, we employed our ELISA that employed the immobilized MBP(84-104) peptide as bait [42]. We have previously identi ed MBP(84-104) as the most potent pro-algesic MBP peptide in females rats [14,31,43].…”

“…Previously, we reported a gradual increase in serum immunoglobulin (Ig)M autoantibody against MBP(84-104) in female rats with CCI [42]. Further, MBP(84-104) exposure in sciatic nerve activated the B cell receptor pathway preferentially in female rodents [43]. Herein, using female and male rats post-CCI, we demonstrate that effect of IV RTX therapy on neuropathic pain and production of IgM autoantibodies against MBP(84-104) are sexually dimorphic (female-speci c).…”

Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action

“…After demonstrating that the injection of MBP 84–104 fragment into naïve nerves induced an ipsilateral inflammatory and immune cascade, Liu et al (2012) postulated that nerve injury and repeated exposure of this hidden region on MBP led to a deleterious, allodynia-reinforcing immune reaction (Liu et al, 2012b). Expanding on this, Chernov et al (2018) interestingly demonstrated that sciatic nerve injection of the MBP 84–104 fragment induced long-lasting mechanical allodynia in female, but not male animals (Chernov et al, 2018). Moreover, they also observed sexual dimorphism in gene expression profiles measured in the sciatic nerve, DRG and spinal cord post injection.…”