IGFBP2-Ceramide Pathway Mediates Divergent Myelin Breakdown in the PNS and CNS Following Injury

Following injury, the peripheral nervous system (PNS) exhibits remarkable regenerative capacity, whereas the central nervous system (CNS) has limited regenerative potential. This difference is partially attributed to distinct postinjury myelin breakdown. However, the underlying mechanisms driving this disparity remain unclear. By comparing the expression profiles of injured peripheral and central nerves in adult male and female C57BL/6J mice, we identified insulin-like growth factor-binding protein 2 (IGFBP2) as a key regulator that determines the differences in myelin breakdown between the injured PNS and CNS. Schwann cell-derived IGFBP2 in the injured PNS promotes myelin breakdown and facilitates axonal regeneration. Furthermore, through lipidomics, we identify ceramide, a sphingolipid regulated by ceramide synthase 6 in injured nerves, as playing a critical role in IGFBP2-mediated myelin breakdown. Conversely, minimal IGFBP2 expression is observed in the injured CNS, contributing to the limited myelin breakdown and axon regeneration in injured CNS. These findings provide insights into the divergent regenerative potential of the PNS and CNS and unveil IGFBP2 and ceramide as promising targets for promoting CNS regeneration after injury.