A heterogeneous subtype of biliary epithelial senescence may be involved in the pathogenesis of primary biliary cholangitis

IF 2.6 4区医学 Q2 GASTROENTEROLOGY & HEPATOLOGY

Clinics and research in hepatology and gastroenterology Pub Date : 2025-01-01 DOI:10.1016/j.clinre.2024.102512

Motoko Sasaki , Yasunori Sato , Yasuni Nakanuma

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引用次数: 0

Abstract

Background & aims

Biliary epithelial senescence is involved in the pathogenesis of primary biliary cholangitis (PBC). We hypothesized that a unique subtype of programmed death-ligand 1 (PD-L1)-positive senescent biliary epithelial cells (BECs) may be related to the pathogenesis of PBC in association with cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) pathway.

Approach & results

The expression of PD-L1, STING and their association with senescent markers p16^INK4a and p21^WAF1/Cip1 were immunohistochemically determined in livers taken from the patients with PBC (n = 87) and 97 diseased and normal control livers. The expression of PD-L1 was significantly increased in a part of senescent BECs with p21^WAF1/Cip1 expression in BECs in the damaged small bile ducts in PBC, compared to control livers (p < 0.01). In contrast, PD-L1 was not expressed in BECs in ductular reactions. The expression of STING was significantly increased in BECs in small bile ducts and ductular reactions in PBC, compared to control livers (p < 0.01). The expression of PD-L1, STING and senescence associated secretory phenotypes (SASPs) including interferon (IFN)-beta was significantly increased in senescent BECs induced by a treatment with serum depletion or glycochenodeoxycholic acid (GCDC) for 4–7 days (p < 0.01) and the increase was significantly suppressed by a knockdown of STING using siRNA (p < 0.01). Induction of cellular senescence induced by a treatment with serum depletion or GCDC was significantly suppressed by a knockdown of STING in BECs. (p < 0.01).

Conclusion

A unique subtype of senescent BECs with PD-L1 expression associated with cGAS-STING pathway may be involved in the pathogenesis of PBC.

查看原文本刊更多论文

胆道上皮衰老的异质性亚型可能参与原发性胆道胆管炎的发病机制。

背景与目的：胆道上皮衰老参与原发性胆道胆管炎（PBC）的发病机制。我们假设程序性死亡配体1 （PD-L1）阳性的衰老胆道上皮细胞（BECs）的一个独特亚型可能与PBC的发病机制有关，该亚型与环GMP-AMP合成酶(cGAS)-干扰素基因刺激因子（STING）通路有关。方法与结果：采用免疫组织化学方法检测了PBC患者（87例）和97例患病及正常对照肝脏中PD-L1、STING的表达及其与衰老标志物p16INK4a和p21WAF1/Cip1的关系。与对照组相比，PBC受损小胆管中部分表达p21WAF1/Cip1的衰老BECs中PD-L1的表达显著升高(PBC结论：一种独特的与cGAS-STING通路相关的PD-L1表达的衰老BECs亚型可能参与了PBC的发病机制。

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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来源期刊

Clinics and research in hepatology and gastroenterology GASTROENTEROLOGY & HEPATOLOGY-

CiteScore

4.30

自引率

3.70%

发文量

198

审稿时长

42 days

期刊介绍： Clinics and Research in Hepatology and Gastroenterology publishes high-quality original research papers in the field of hepatology and gastroenterology. The editors put the accent on rapid communication of new research and clinical developments and so called "hot topic" issues. Following a clear Editorial line, besides original articles and case reports, each issue features editorials, commentaries and reviews. The journal encourages research and discussion between all those involved in the specialty on an international level. All articles are peer reviewed by international experts, the articles in press are online and indexed in the international databases (Current Contents, Pubmed, Scopus, Science Direct). Clinics and Research in Hepatology and Gastroenterology is a subscription journal (with optional open access), which allows you to publish your research without any cost to you (unless you proactively chose the open access option). Your article will be available to all researchers around the globe whose institution has a subscription to the journal.