Primary sclerosing cholangitis (PSC) is a chronic idiopathic cholestatic liver disease characterized by biliary inflammation and stricture-formation and hepatic fibrosis/cirrhosis. Recurrent episodes of intestinal inflammation, mostly corresponding to ulcerative colitis (UC), are frequently observed. The etiopathogenesis of the disease and the driving force behind the concomitant presentation have not been elucidated but both are classified as multifactorial immune-related diseases in which the gut-liver crosstalk is compromised. The role of macrophages has been implemented in disease pathogenesis and we have recently identified Trem2 as an important macrophage marker in experimental models for sclerosing cholangitis and colitis. In this project, we will further extend these data, unravel the immunological profile of PSC, UC and PSC-UC patients at the single cell level, explore the role of specific monocyte/macrophage populations and that of macrophage-Trem2 in sclerosing cholangitis and related ulcerative colitis. To this end, we will use an unbiased approach of single cell technologies on human samples and use transgenic approaches and in vitro assays to address the role of monocyte/macrophage populations and macrophage-Trem2 in sclerosing cholangitis and associated colitis.