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USP50在十二指肠-胃反流诱导的胃癌发生过程中调节NLRP3炎性小体的激活。

USP50 regulates NLRP3 inflammasome activation in duodenogastric reflux-induced gastric tumorigenesis.

作者信息

Zhao Chenye, Mu Mingchao, Li Xiaopeng, Dong Zepeng, Wang Jiahao, Yao Chengzhi, Zheng Jianbao, Sun Xuejun, Yu Junhui

机构信息

Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

出版信息

Front Immunol. 2024 Feb 26;15:1326137. doi: 10.3389/fimmu.2024.1326137. eCollection 2024.

DOI:10.3389/fimmu.2024.1326137
PMID:38469295
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10925683/
Abstract

Duodenogastric reflux (DGR) has been linked to the onset of gastric cancer (GC), although the precise mechanism is yet obscure. Herein, we aimed to investigate how refluxed bile acids (BAs) and macrophages are involved in gastric carcinogenesis. In both active human bile reflux gastritis and the murine DGR model, ubiquitin specific protease 50 (USP50) was dramatically raised, and macrophages were the principal leukocyte subset that upregulated USP50 expression. Enhancing USP50 expression amplified bile acid-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and subsequent high-mobility group box protein 1 (HMGB1) release, while USP50 deficiency resulted in the reversed alteration. Mechanistically, USP50 interacted with and deubiquitinated apoptosis-associated speck-like protein containing CARD (ASC) to activate NLRP3 inflammasome. The release of HMGB1 contributes to gastric tumorigenesis by PI3K/AKT and MAPK/ERK pathways. These results may provide new insights into bile reflux-related gastric carcinogenesis and options for the prevention of DGR-associated GC.

摘要

十二指肠-胃反流（DGR）与胃癌（GC）的发生有关，尽管确切机制尚不清楚。在此，我们旨在研究反流胆汁酸（BAs）和巨噬细胞如何参与胃癌发生。在活动性人类胆汁反流性胃炎和小鼠DGR模型中，泛素特异性蛋白酶50（USP50）显著升高，巨噬细胞是上调USP50表达的主要白细胞亚群。增强USP50表达可放大胆汁酸诱导的含NLR家族pyrin结构域3（NLRP3）炎性小体激活及随后的高迁移率族蛋白B1（HMGB1）释放，而USP50缺乏则导致相反的改变。机制上，USP50与含CARD的凋亡相关斑点样蛋白（ASC）相互作用并使其去泛素化，以激活NLRP3炎性小体。HMGB1的释放通过PI3K/AKT和MAPK/ERK途径促进胃癌发生。这些结果可能为胆汁反流相关胃癌发生提供新见解，并为预防DGR相关GC提供选择。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/cfe91e8a274c/fimmu-15-1326137-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/1064d6b2268c/fimmu-15-1326137-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/4e0b5f6e1e06/fimmu-15-1326137-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/f4d46026bf75/fimmu-15-1326137-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/0b3608a31ef2/fimmu-15-1326137-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/0bd4257db4ed/fimmu-15-1326137-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/f1d5a5609a82/fimmu-15-1326137-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/cfe91e8a274c/fimmu-15-1326137-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/1064d6b2268c/fimmu-15-1326137-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/4e0b5f6e1e06/fimmu-15-1326137-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/f4d46026bf75/fimmu-15-1326137-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/0b3608a31ef2/fimmu-15-1326137-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/0bd4257db4ed/fimmu-15-1326137-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/f1d5a5609a82/fimmu-15-1326137-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3007/10925683/cfe91e8a274c/fimmu-15-1326137-g007.jpg

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