Inhibition of CXCR2 improves motor coordination through attenuating white matter lesions in Parkinson's disease models.

White matter lesions (WMLs) are increasingly recognized as early and critical pathological features of Parkinson's disease (PD). C-X-C motif chemokine receptor 2 (Cxcr2) plays an important role in regulating oligodendrocyte progenitor cell (OPC) maturation and WMLs repair. However, the functional roles and underlying mechanisms of Cxcr2 in the pathogenesis of PD remain unclear. In the present study, we demonstrated that Cxcr2 expression progressively increased with PD progression across multiple PD models and was positively correlated with the severity of WMLs. Pharmacological inhibition of Cxcr2 with SB225002 promoted OPC differentiation and myelin repair, thereby alleviating WMLs and gait disturbances in MPTP-induced PD mice. These improvements further contributed to the attenuation of dopaminergic neurodegeneration and nigrostriatal pathway-related motor deficits in PD mice. Proteomic analysis identified synaptojanin 1 (Synj1) as a key downstream effector of Cxcr2 in OPCs. We revealed that inhibition of Cxcr2 could promote oligodendrocyte-neuron communication via Synj1-mediated vesicular transport, thereby preserving axonal integrity and neuronal function. In conclusion, this study uncovered the protective role and mechanisms of Cxcr2 inhibition on dopaminergic neurons through attenuating WMLs, highlighting Cxcr2 as a potential therapeutic target for PD.