CCL17/CCR4 Axis Promotes Hematoma Clearance via ERK/AP1/SRA-Mediated Microglial Polarization After Intracerebral...

Our previous studies demonstrated that CCL17 and its receptor CCR4 play crucial roles in neuroinflammation and microglial activation following intracerebral hemorrhage (ICH). However, the specific mechanisms by which the CCL17/CCR4 axis regulates microglial polarization and hematoma clearance remain unclear.

This study investigates how the CCL17/CCR4 signaling pathway modulates microglial phenotype transition and enhances hematoma resolution after ICH, building upon our earlier findings showing CCR4's involvement in neuroinflammatory responses.

Using CRISPR-mediated CCR4 disruption and CCR4 overexpression approaches in a mouse ICH model, we examined neurological outcomes, inflammatory responses, and hematoma volumes. We further evaluated the therapeutic potential of recombinant CCL17 administration. The downstream ERK signaling pathway's role in CCL17/CCR4-mediated microglial function was investigated through pharmacological inhibition.

CCR4 knockout exacerbated neurological deficits, increased neuroinflammation, and enlarged hematomas. In contrast, enhancing CCR4 expression or administering recombinant CCL17 improved functional recovery and provided neuroprotection. Mechanistically, CCL17/CCR4 signaling activated the ERK/AP1/SRA pathway, promoting anti-inflammatory, phagocytic microglial polarization, evidenced by increased CD206 and SRA expression. ERK inhibition reversed these protective effects.

Our findings extend previous work by revealing that the CCL17/CCR4 axis enhances hematoma clearance through the ERK/AP1/SRA pathway-mediated microglial polarization. This mechanism represents a promising therapeutic target for ICH treatment.