Inactivation of LCN2/EGR1 Promotes Oligodendrocyte Progenitor Cell Differentiation and Remyelination after White Matter Injury

The insufficient remyelination due to impaired oligodendrocyte precursor cell (OPC) differentiation and maturation is highly associated with irreversible white matter injury (WMI) and neurological deficits. Consequently, inhibitory microenvironment for remyelination might serve as potential therapeutic targets for treating WMI after acute central nervous system injury and neurodegeneration diseases. We found genetic inhibition of the increase in Lipocalin-2 promoted OPC differentiation, remyelination, and functional recovery after both atypical, acute WMI disease subarachnoid hemorrhage (SAH) and typical, chronic WMI disease multiple sclerosis (MS). Lipocalin-2 was shown to activate Early Growth Response Protein-1 (EGR1) in OPCs, which is partly regulated by its receptor SLC22A17. In the conditional knockout of EGR1 in OPCs, enhanced OPC differentiation in developing and injured white matter; consistently, the specific inactivation of EGR1 promoted remyelination and neurological recovery after SAH or MS. Thus, we propose that following WMI in humans, the increase in Lipocalin-2 activates EGR1 and consequently impair OPC differentiation and myelin repair. Our results suggest therapies specifically inactivating Lipocalin-2/EGR1 signal in oligodendroglial lineage cells could represent a novel strategy to enhance differentiation and remyelination in WMI patients.