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

Background: 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.

Aims: 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.

Methods: 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.

Results: 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.

Conclusion: 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.