HMGB1 induces mitochondrial dysfunction through the TLR4 and RAGE pathways to promote astrocyte autophagy and PANoptosis in intracerebral hemorrhage
Wenzuo Shang, Jingyu Cui, Xueling Bai, Le Cao, Mangmang Xu, Shuai Jiang, Bo WuAbstract
Background:
Secondary injury is an important factor that leads to a poor prognosis of intracerebral hemorrhage (ICH). Programmed cell death (PCD) plays an important role in secondary injury. After ICH, hyperactivated astrocytes transition from a protective role to a proinflammatory state, releasing neurotoxic factors that amplify neuroinflammation and exacerbate neurological deficits. Through multi-omics sequencing, we found High-mobility group box 1 (HMGB1)may be a key factor . In this study, we investigated its regulatory role in ICH and different PCDs.
Methods:
The ICH model was established by collagenase injection
Results:
The results showed that after ICH, HMGB1 translocated from the nucleus to the cytoplasm and extracellular space. Extracellular HMGB1 upregulated the expression of related molecules, increased the corresponding pathological changes. Multi-omics sequencing suggested that mitochondrial function-related pathways were enriched after ICH. Results showed that increased extracellular HMGB1 aggravated mitochondrial morphology and functional damage and the expression and release of inflammatory factors. Inhibiting TLR4 and RAGE pathways alleviated the HMGB1-mediated injuries.
Conclusion:
In the acute phase of ICH, HMGB1 promoted poor prognosis by mediating mitochondrial dysfunction through the TLR4 and RAGE pathways, thereby promoting autophagy and PANoptosis while increasing neuroinflammation after ICH.