CCR2 knockdown attenuates post-hemorrhagic hydrocephalus and improves glymphatic function after intraventricular hemorrhage.

Post-hemorrhagic hydrocephalus (PHH) is a severe complication of intraventricular hemorrhage (IVH), yet its underlying mechanisms remain unclear. The glymphatic system (GS), a key pathway involved in cerebrospinal fluid (CSF) circulation and metabolic waste clearance, has recently been implicated in the pathogenesis of PHH. In this study, we employed a mouse model of IVH (n = 6 per group, assessed from 6 h to 28 days post-IVH) to investigate the role of the CCL2/CCR2 signaling axis in GS dysfunction and PHH progression. Behavioral tests, CSF tracer imaging, immunofluorescence, and Western blot analyses were used to assess CSF dynamics, AQP4 polarization, and relevant protein levels. The results showed that IVH induced upregulation of CCL2/CCR2, endoplasmic reticulum stress, and NF-κB activation, accompanied by the loss of AQP4 polarization and impairment of GS function. Notably, CCR2 inhibition was significantly associated with restored AQP4 polarization, improved CSF clearance, reduced ventricular enlargement, and ameliorated neurological deficits. These findings suggest that the CCL2/CCR2 signaling pathway may contribute to GS dysfunction in PHH and provide a foundation for exploring its therapeutic potential.