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

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.