Mapping the hepatic immune landscape identifies monocytic macrophages as key drivers of steatohepatitis and cholangiopathy progression

作者：Adrien Guillot, Marc Winkler, Milessa Silva Afonso, Abhishek Aggarwal, David López, Hilmar Berger, Marlene Kohlhepp, Hanyang Liu, Burcin Özdirik, Johannes Eschrich, Jing Ma, Moritz Peiseler, Felix Heymann, Swetha Pendem, Sangeetha Mahadevan, Bin Gao, Lauri Diehl, Ruchi Gupta, Frank Tacke · 发表于：Hepatology · 年份：2023 · DOI：10.1097/hep.0000000000000270 · 被引用次数：108 · 研究领域：Liver Diseases and Immunity、Liver Disease Diagnosis and Treatment、Liver physiology and pathology

BACKGROUND AND AIMS: The progression of chronic liver diseases towards liver cirrhosis is accompanied by drastic tissue changes. This study combines elaborate transcriptomic and histological methods aiming at spatially resolving the hepatic immune microenvironment in NAFLD (including NASH, primary sclerosing cholangitis, primary biliary cholangitis, and severe alcoholic hepatitis). APPROACH AND RESULTS: Human liver samples were subjected to RNA-sequencing (n=225) and imaging cytometry (n=99) across 3 independent patient cohorts. Liver samples from alcoholic hepatitis and primary biliary cholangitis patients were used for comparison. Myeloid populations were further characterized in corresponding mouse models. Imaging, clinical, and phenotypical data were combined for multidimensional analysis. NAFLD/NASH and primary sclerosing cholangitis disease stages were associated with loss of parenchymal areas, increased ductular cell accumulation, and infiltration of immune cells. NASH patients predominantly exhibited myeloid cell accumulation, whereas primary sclerosing cholangitis patients additionally had pronounced lymphoid cell responses. Correlating to disease stage, both etiologies displayed intense IBA1 + CD16 low CD163 low macrophage aggregation in nonparenchymal areas, with a distinct spatial proximity to ductular cells. Mouse models revealed that disease-associated IBA1 + hepatic macrophages originated from bone marrow-derived monocytes. Using an unbiased, machine learning-b...