Abstract
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease. Approximately 30% of patients do not respond to therapy with ursodeoxycholic acid (UDCA). Previous studies have implicated increased senescence of cholangiocytes in patients who do not respond to UDCA. This may increase the release of cytokines which drive pathogenic T cell polarization. As FXR agonists are beneficial in treating UDCA non‐responsive patients, the current study was designed to model the interactions between cholangiocytes and CD4+ T cells to investigate potential immunomodulatory mechanisms of bile acid receptor agonists. Human cholangiocytes were co‐cultured with CD4+ T cells to model the biliary stress response. Senescent cholangiocytes were able to polarize T cells toward a Th17 phenotype and suppressed expression of FoxP3 (P = 0.0043). Whilst FXR and TGR5 receptor agonists were unable directly to alter cholangiocyte cytokine expression, FGF19 was capable of significantly reducing IL‐6 release (P = 0.044). Bile acid receptor expression was assessed in PBC patients with well‐characterized responsiveness to UDCA therapy. A reduction in FXR staining was observed in both cholangiocytes and hepatocytes in PBC patients without adequate response to UDCA. Increased IL‐6 expression by senescent cholangiocytes represents a potential mechanism by which biliary damage in PBC could contribute to excessive inflammation.
Highlights
Cholangiocyte senescence has been observed previously in various liver diseases as a response to ongoing damage in the biliary epithelium.[1,2,3] When senescent, cholangiocytes secrete a milieu of cytokines and chemokines, referred to as the senescence‐associated secretory phenotype (SASP).[3,4,5] Of note, the SASP of cholangiocytes consists of a number of cytokines and chemokines involved in CD4+ T helper (Th) cell responses
The data presented in this paper show that the biliary SASP may be contributing to the pathogenic T cell phenotype reported in Primary biliary cholangitis (PBC) patients
Immunohistochemistry on PBC patients has previously demonstrated release of cytokines typically associated with Th17 cells, IL‐6, IL‐23, and CCL20.1,5,12 We found that many of these cytokines were up‐regulated by the cholangiocytes following senescence induction, IL‐6 was by far the most abundant
Summary
Cholangiocyte senescence has been observed previously in various liver diseases as a response to ongoing damage in the biliary epithelium.[1,2,3] When senescent, cholangiocytes secrete a milieu of cytokines and chemokines, referred to as the senescence‐associated secretory phenotype (SASP).[3,4,5] Of note, the SASP of cholangiocytes consists of a number of cytokines and chemokines involved in CD4+ T helper (Th) cell responses. Whilst FXR and TGR5 receptor agonists were unable directly to alter cholangiocyte cytokine expression, FGF19 was capable of significantly reducing IL‐6 release (P = 0.044).
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