Abstract
Background: Cerebral arteriovenous malformations (cAVMs) are complex vascular anomalies carrying a high risk of hemorrhage due to abnormal arteriovenous connections. Recent studies have highlighted the roles of inflammation and KRAS mutations in the pathogenesis of cAVM. Necroptosis is a programmed cell necrosis pathway mediated by RIPK3 (receptor-interacting protein kinase 3) and MLKL (mixed-lineage kinase domain-like protein). The pathway, which is inhibited by caspase-8, plays multifunctional roles in various diseases. However, the involvement of necroptosis and its relationship with caspase-8 in the pathogenesis of cAVM remain unclear. Methods: We analyzed tissue samples from 23 patients with cAVM in comparison with normal brain tissues. Proteome profiling, immunohistochemistry, and quantitative polymerase chain reaction assays were used to assess the expression of inflammatory molecules and programmed cell death markers. Results: Protein and gene expression of necroptosis-related molecules (RIPK3, MLKL), caspase-8, and IL-6 (interleukin-6) and IL-8 were significantly elevated in cAVM nidi compared with normal brain tissue. High MLKL protein expression was associated with severe clinical presentations and hemorrhage, whereas caspase-8 protein expression was elevated in less-severe cases and unruptured cAVM. Conclusion: Our analysis of human samples offers the first evidence of necroptosis-related molecules acting against caspase-8 in association with the inflammatory cytokines IL-6 and IL-8 in the pathogenesis of cAVM. The balance between MLKL and caspase-8 expression may be linked to the clinical condition and hemorrhagic presentation of patients with cAVM on admission.