Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH

作者：Tim Hendrikx, Florentina Porsch, Máté G. Kiss, Dragana Rajcic, Nikolina Papac-Miličević, Constanze Hoebinger, Laura Goederle, Anastasiya Hladik, Lisa E. Shaw, Hauke Horstmann, Sylvia Knapp, Sophia Derdak, Martin Bilban, Lena Heintz, Marcin Krawczyk, Rafael Paternostro, Michael Trauner, Matthias Farlik, Dennis Wolf, Christoph J. Binder · 发表于：Journal of Hepatology · 年份：2022 · DOI：10.1016/j.jhep.2022.06.004 · 被引用次数：208 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Inflammation biomarkers and pathways、Immune cells in cancer

Background & Aims Previous single-cell RNA-sequencing analyses have shown that Trem2 -expressing macrophages are present in the liver during obesity, non-alcoholic steatohepatitis (NASH) and cirrhosis. Herein, we aimed to functionally characterize the role of bone marrow-derived TREM2-expressing macrophage populations in NASH. Methods We used bulk RNA sequencing to assess the hepatic molecular response to lipid-dependent dietary intervention in mice. Spatial mapping, bone marrow transplantation in two complementary murine models and single-cell sequencing were applied to functionally characterize the role of TREM2 + macrophage populations in NASH. Results We found that the hepatic transcriptomic profile during steatohepatitis mirrors the dynamics of recruited bone marrow-derived monocytes that already acquire increased expression of Trem2 in the circulation. Increased Trem2 expression was reflected by elevated levels of systemic soluble TREM2 in mice and humans with NASH. In addition, soluble TREM2 levels were superior to traditionally used laboratory parameters for distinguishing between different fatty liver disease stages in two separate clinical cohorts. Spatial transcriptomics revealed that TREM2 + macrophages localize to sites of hepatocellular damage, inflammation and fibrosis in the steatotic liver. Finally, using multiple murine models and in vitro experiments, we demonstrate that hematopoietic Trem2 deficiency causes defective lipid handling and extracellular matrix...