Interleukin-8–Driven Monocyte Activation in Primary Sclerosing Cholangitis: Insights from Single-Cell Analysis and Humanized Immune System Mice

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease with an incompletely understood pathogenesis. Monocyte/macrophage cell dysregulation has been suggested to contribute, 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 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. METHODS: Peripheral blood mononuclear cells from PSC and ulcerative colitis patients and from healthy controls were profiled using 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. RESULTS: macrophages were expanded during disease progression (p<0.05). Pharmacologic Cxcr1 antagonism in conventional rodent immune system and antibody-mediated IL-8 neutralization in HIS mice reduced cholestatic liver injury. CONCLUSIONS: 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 may represent a promising therapeutic strategy and urges further investigation.