Sasaki Motoko, Sato Yasunori, Nakanuma Yasuni
Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.
Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.
Clin Res Hepatol Gastroenterol. 2025 Jan;49(1):102512. doi: 10.1016/j.clinre.2024.102512. Epub 2024 Dec 9.
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 and p21 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 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).
A unique subtype of senescent BECs with PD-L1 expression associated with cGAS-STING pathway may be involved in the pathogenesis of PBC.
胆管上皮细胞衰老参与原发性胆汁性胆管炎（PBC）的发病机制。我们假设程序性死亡配体1（PD-L1）阳性的衰老胆管上皮细胞（BECs）的一种独特亚型可能与PBC的发病机制有关，并与环磷酸鸟苷-腺苷酸合成酶（cGAS）-干扰素基因刺激因子（STING）途径相关。
采用免疫组织化学方法检测87例PBC患者肝脏以及97例病变和正常对照肝脏中PD-L1、STING的表达及其与衰老标志物p16和p21的关系。与对照肝脏相比，PBC患者受损小胆管中部分表达p21的衰老BECs中PD-L1的表达显著增加（p<0.01）。相比之下，PD-L1在胆管反应中的BECs中不表达。与对照肝脏相比，PBC患者小胆管和胆管反应中的BECs中STING的表达显著增加（p<0.01）。用血清饥饿或甘氨鹅去氧胆酸（GCDC）处理4-7天诱导的衰老BECs中，PD-L1、STING的表达以及包括干扰素（IFN）-β在内的衰老相关分泌表型（SASPs）显著增加（p<0.01），并且使用小干扰RNA（siRNA）敲低STING可显著抑制这种增加（p<0.01）。在BECs中敲低STING可显著抑制血清饥饿或GCDC处理诱导的细胞衰老（p<0.01）。
一种与cGAS-STING途径相关且表达PD-L1的独特衰老BECs亚型可能参与PBC的发病机制。
