Intracerebral hemorrhage (ICH) is a devastating disease that disrupts the blood-brain barrier (BBB), triggers inflammation, and leads to subsequent neurological deficits. Although the CXC chemokine receptor 3 (CXCR3) and its ligand CXCL10 are implicated in regulating inflammation, the specific role and mechanism of CXCR3 in ICH-induced BBB disruption remain unclear; furthermore, the involvement of the cGAS/AIM2 signaling pathway in endothelial pyroptosis after ICH needs further investigation. This study elucidates that activation of the CXCR3/CXCL10 axis exacerbates disruption of BBB integrity via the cGAS/AIM2 pathway following ICH. Utilizing a type IV collagenase-induced ICH model, we evaluated the therapeutic efficacy of the CXCR3 inhibitor AMG487. Results demonstrated that ICH induced the upregulation of CXCR3 and CXCL10, peaking at 24 h; immunofluorescence co-localization indicated CXCR3 was primarily localized to endothelial cells, while CXCL10 originated mainly from endothelial cells and astrocytes. AMG487 treatment improved neurological deficits and attenuated BBB disruption after ICH. Furthermore, exogenous CXCL10 activating CXCR3 upregulated the expression of cGAS/STING and pyroptosis-related proteins in vivo and vitro ICH models. However, inhibiting CXCR3 reversed the poor effects induced by CXCL10. Inhibition of the cGAS/AIM2 signaling pathway using A151 effectively reduced vascular endothelial pyroptosis and BBB disruption. In a co-culture model of endothelial cells and astrocytes, depleting CXCL10 downregulated the expression of cGAS, STING, AIM2, and pyroptosis-related proteins and alleviated endothelial pyroptosis. This study demonstrates that inhibition CXCR3 preserves BBB integrity and improves neurological deficits after ICH by suppressing endothelial pyroptosis via the cGAS/AIM2 signaling pathway. These findings provide novel insights into ICH pathogenesis, proposing CXCR3 as a potential target for BBB disruption and AMG487 as a promising therapeutic strategy for ICH patients.
Sheng et al. (Fri,) studied this question.