The Interleukin-17-T helper 17 axis in primary sclerosing cholangitis: A narrative review of an emerging pathogenic...

Interleukin-17 (IL-17) and IL-17+ secretory cells, including T helper 17 (Th17) cells play pivotal roles in autoimmune diseases such as psoriasis. Emerging evidence implicates the IL-17 pathway in primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease lacking approved pharmacological therapies, for which liver transplantation remains the only life-extending option. The IL-17 pathway and Th17 biology is increasingly implicated in PSC pathogenesis through its interactions with hepatic parenchymal and non-parenchymal cells, including cholangiocytes, neutrophils and hepatic stellate cells which promote periductal fibro-inflammation, immune cell recruitment and pro-inflammatory cytokine release. Th17 cells and IL-17+ secreting lymphocytes localise to peribiliary regions, exacerbating biliary injury and fibrosis. Preclinical murine models suggest that inhibition of IL-17 signalling mitigates hepatic fibro-inflammatory responses, providing a compelling rationale for its investigation as a potential therapeutic target in PSC. Whilst licensed IL-17 inhibitors have demonstrated efficacy and safety in a number of autoimmune and immune-mediated diseases, IL-17 has context-dependent roles in tissue homeostasis and host defence underscoring the pathway's complexity. This narrative review synthesises the biology of the IL-17 family, integrating preclinical and translational evidence relevant to PSC, and discusses the translational potential of approved anti-IL-17 agents as novel therapeutic candidates in PSC, whilst highlighting key uncertainties and gastrointestinal safety considerations.