Papers of the Week

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.