Gasdermin D deletion prevents liver injury and exacerbates extrahepatic damage in a murine model of alcohol-induced ACLF.

eGastroenterology Pub Date : 2025-03-22 eCollection Date: 2025-01-01 DOI:10.1136/egastro-2024-100151
Martí Ortega-Ribera, Yuan Zhuang, Veronika Brezani, Radhika S Joshi, Zsuzsanna Zsengeller, Prashanth Thevkar Nagesh, Aditi Datta, Gyongyi Szabo
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Abstract

Background: Gasdermin D (GSDM-D), a key executor of pyroptosis, is increased in various liver diseases and contributes to disease progression. Alcohol induces inflammasome activation and cell death, which are both linked to GSDM-D activation. However, its role in alcohol-induced acute-on-chronic liver failure (ACLF) remains unclear.

Methods: ACLF was induced in GSDM-D-deficient or wild-type (WT) mice by 28-day bile duct ligation surgery plus a single 5 g/kg alcohol binge leading to acute decompensation. Nine hours after the alcohol binge, blood, liver, kidney and cerebellum specimens were collected for analysis.

Results: Active GSDM-D was significantly increased in humans and mice ACLF livers compared with both healthy controls and cirrhotic livers. GSDM-D-deficient mice with ACLF showed decreased inflammation, neutrophil infiltration and fibrosis in the liver, together with a reduction in pyroptotic, apoptotic and necroptotic death, compared with WT ACLF mice. Notably, GSDM-D-deficient mice also showed decreased liver regeneration and hepatocyte function. This was associated with an increase in senescence and expression of stem-like/cholangiocyte markers in the liver. Interestingly, in the kidney, GSDM-D-deficient mice showed an increase in histopathological damage score, decreased function and increased expression of necroptosis-related genes. In the cerebellum, GSDM-D deficiency increased the expression of neuroinflammation markers, astrocyte activation and apoptosis-related genes.

Conclusion: Our data indicate that GSDM-D deficiency has organ-specific effects in ACLF. While it reduces inflammation, neutrophil activation, cell death and fibrosis in the liver, GSDM-D deficiency impairs the synthetic function and increases senescence in hepatocytes. GSDM-D deficiency also increases kidney injury and neuroinflammation in ACLF.

在酒精诱导的小鼠ACLF模型中,Gasdermin D缺失可预防肝损伤并加重肝外损伤。
背景:GSDM-D是肝脏焦亡的关键执行者,在各种肝脏疾病中升高,并有助于疾病进展。酒精诱导炎性体激活和细胞死亡,这两者都与GSDM-D激活有关。然而,其在酒精诱导的急性慢性肝衰竭(ACLF)中的作用尚不清楚。方法:通过28天的胆管结扎手术和单次5 g/kg酒精暴饮导致急性失代偿,在gsdm -d缺陷或野生型(WT)小鼠中诱导ACLF。酗酒9小时后,采集血液、肝脏、肾脏和小脑标本进行分析。结果:与健康对照组和肝硬化肝脏相比,人类和小鼠ACLF肝脏中活性GSDM-D显著增加。与WT ACLF小鼠相比,gsdm -d缺失小鼠表现出肝脏炎症、中性粒细胞浸润和纤维化减少,同时焦亡、凋亡和坏死性死亡减少。值得注意的是,gsdm -d缺陷小鼠也表现出肝脏再生和肝细胞功能下降。这与肝脏中干细胞样/胆管细胞标记物的衰老和表达增加有关。有趣的是,在肾脏中,gsdm -d缺陷小鼠表现出组织病理学损伤评分增加,功能下降和坏死相关基因表达增加。在小脑中,GSDM-D缺乏增加了神经炎症标志物、星形胶质细胞激活和凋亡相关基因的表达。结论:我们的数据表明,GSDM-D缺乏在ACLF中具有器官特异性影响。虽然GSDM-D可以减少肝脏的炎症、中性粒细胞活化、细胞死亡和纤维化,但缺乏GSDM-D会损害肝细胞的合成功能,增加肝细胞的衰老。GSDM-D缺乏也会增加ACLF的肾损伤和神经炎症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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