Tumor necrosis factor-stimulated gene-6 ameliorates early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome-mediated astrocyte pyroptosis

• Published in: Neural regeneration research 2024-05, Vol.19 (5), p.1064-1071
• Main Authors: Ding, Mingxiang, Jin, Lei, Wei, Boyang, Cheng, Wenping, Liu, Wenchao, Li, Xifeng, Duan, Chuanzhi
• Format: Article
• Language: English
• Subjects: Edema; Hemorrhage; Traumatic brain injury; Tumor necrosis factor-TNF
• ISSN: 1673-5374; 1876-7958
• DOI: 10.4103/1673-5374.385311

Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment. Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage. Previous studies have confirmed that tumor necrosis factor-stimulated gene-6 (TSG-6) can exert a neuroprotective effect by suppressing oxidative stress and apoptosis. However, no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage. In this study, a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method. Our results indicated that TSG-6 expression was predominantly detected in astrocytes, along with NLRC4 and gasdermin-D (GSDMD). The expression of NLRC4, GSDMD and its N-terminal domain (GSDMD-N), and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment. To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage, recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles. Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits. Moreover, TSG-6 knockdown further increased the expression of NLRC4, which was accompanied by more severe astrocyte pyroptosis. In summary, our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.