Interleukin-8-driven monocyte activation in primary sclerosing cholangitis: Insights from single-cell analysis and...

Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease with an incompletely understood pathogenesis. Dysregulation of monocytes and macrophages has been implicated in disease development, although their functional relevance remains insufficiently understood. The main aim of this study was to identify peripheral myeloid cell populations involved in PSC pathogenesis and to assess the therapeutic potential of targeting associated inflammatory signalling pathways. Additionally, we sought to enhance translational relevance through the application of a humanized immune system (HIS) mouse model.

Peripheral blood mononuclear cells from patients with PSC, patients with ulcerative colitis, and healthy controls were profiled using CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing). Inflammatory signalling via the IL-8:CXCR1/2 axis was further evaluated in both conventional and HIS mouse models of cholestatic liver disease.

Patients with PSC exhibit a population of circulatory CXCL8⁺CD14⁺ monocytes with upregulated proinflammatory signalling. Serum concentrations of the proinflammatory cytokine IL-8, encoded by CXCL8, were increased in patients with PSC (p <0.001) and associated with poor prognosis. Patients with high IL-8 concentrations (≥27.8 pg/ml) at baseline had significantly worse transplant-free survival than those with lower IL-8 concentrations (log-rank hazard ratio 6.12, 95% CI 1.68-22.33). Intrahepatic IL-8⁺ macrophages were expanded during disease progression (p <0.05). Pharmacological Cxcr1 antagonism in conventional mouse models and antibody-mediated IL-8 neutralization in HIS mice reduced cholestatic liver injury.

A circulating CXCL8⁺CD14⁺ monocyte subset and intrahepatic IL-8⁺ macrophages were identified as potential contributors to PSC pathogenesis. HIS mouse models could mark a significant advance in translational research on human immune responses. Targeting the IL-8:CXCR1/2 axis represents a promising therapeutic strategy that warrants further investigation.

The immune mechanisms underlying primary sclerosing cholangitis (PSC) remain incompletely understood, limiting the development of effective targeted therapies. We identified a circulating CXCL8⁺CD14⁺ monocyte subset and expanded intrahepatic IL-8⁺ macrophages associated with inflammatory activation in PSC, while elevated serum IL-8 concentrations identified patients with poorer transplant-free survival. Therapeutic inhibition of the IL-8:CXCR1/2 axis reduced cholestatic liver injury in both conventional and humanized immune system mouse models, supporting its relevance across experimental systems. These findings implicate IL-8-driven myeloid inflammation in PSC pathogenesis, identify IL-8 as a potential prognostic biomarker, and support further evaluation of IL-8-directed therapies in PSC.