Primary sclerosing cholangitis (PSC) is a chronic idiopathic cholestatic liver disease characterized by biliary inflammation, stricture-formation and hepatic fibrosis/cirrhosis. The pathogenesis of PSC is only partly understood but aberrant immune cell infiltration and dysregulated immune responses are present. Therefore, PSC is considered an immune-mediated disease and the involvement of components of the immune system to disease progression is subject of intense investigation. Macrophages have been implemented in PSC pathogenesis and we recently found an outspoken presence of osteopontin-positive bile duct-associated macrophages in experimental models for PSC. Osteopontin is a pleiotropic cytokine, adhesion molecule and intracellular signalling mediator with both inflammatory and fibrogenic properties and has been implemented in chronic liver disease progression. In this project, we want to further unravel the role of osteopontin in macrophages and the origin and contribution of osteopontin-positive macrophages in PSC pathogenesis. For this, we will use advanced transgenic mice, relevant mouse models for PSC and in vitro assays. In addition, we will characterize osteopontin-positive macrophages in the liver of human PSC patients and explore its potential as serum biomarker for PSC to strengthen translation to the clinic.