Abstract

The insufficient remyelination due to the impaired oligodendrocyte precursor cell differentiation and maturation is highly associated with irreversible white matter injury and neurological deficits. Consequently, inhibitory components and microenvironment for remyelination might serve as potential therapeutic targets for treating white matter injury after acute central nervous system injury and neurodegeneration diseases. Lipocalin-2 was recently reported to corelate with white matter in both atypical, acute white matter injured disease subarachnoid hemorrhage and typical, chronic white matter injured disease multiple sclerosis. To elucidate the role and underlying mechanism of Lipocalin-2 in oligodendrocyte precursor cell differentiation and remyelination, we used genetic inhibition and a constitutive conditional knockout model with subarachnoid hemorrhage or multiple sclerosis. We found that the genetic inhibition of the increase in Lipocalin-2 promoted oligodendrocyte precursor cell differentiation, remyelination, and functional recovery after subarachnoid hemorrhage or multiple sclerosis. Unexpectedly, the inhibition of Lipocalin-2 did not reduce glial activation and inflammation. Lipocalin-2 was shown to activate Early Growth Response Protein 1 in oligodendrocyte precursor cells, which is partly regulated by its receptor SLC22A17. In the conditional knockout of Early Growth Response Protein 1 in oligodendrocyte precursor cells, we discovered enhanced oligodendrocyte precursor cell differentiation in developing and injured white matter; consistently, the specific inactivation of Early Growth Response Protein 1 promoted remyelination and neurological recovery after subarachnoid hemorrhage or multiple sclerosis. Thus, we propose that following white matter injury in humans, the increase in Lipocalin-2 activates Early Growth Response Protein 1 and consequently impair oligodendrocyte precursor cell differentiation and myelin repair. Our results suggest that therapies specifically inactivating Lipocalin-2/ Early Growth Response Protein 1 signal in oligodendroglial lineage cells could represent a novel strategy to enhance differentiation and remyelination in white matter injury patients.