| Abstract: | BACKGROUND & AIMS: Due to the complex multifactorial origin and an incomplete understanding of the underlying disease mechanisms, progression of non-alcoholic fatty liver disease (NAFLD) into advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis is predicted to become the primary indication for liver transplantation. Hence, there is an unmet need to identify novel targets to improve treatment strategies. METHODS: In an unbiased approach using bulk RNA sequencing, the hepatic molecular response to lipid-dependent dietary intervention was assessed in mice. Spatial mapping, bone marrow transplantation in two complementary murine models and single cell sequencing was applied to functionally characterize the role of bone marrow-derived 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 circulation. Increased Trem2 expression was reflected by elevated levels of systemic soluble TREM2 in mice and humans with NASH. In addition, soluble TREM2 levels transpire as a superior marker over traditionally used laboratory parameters to distinguish between different fatty liver disease stages of NAFLD 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 remodeling, resulting in exacerbated steatohepatitis, cell death and fibrosis. CONCLUSIONS: Our study highlights the functional properties of bone marrow-derived TREM2+ macrophages and implies the clinical relevance of systemic soluble TREM2 levels in the context of NASH. LAY SUMMARY: Our study defines the origin and function of hepatic TREM2+ macrophages and describes a mechanism by which they are critically involved in protecting from NASH. Furthermore, our data show that systemic soluble TREM2 levels mirror the dynamics of liver infiltrating TREM2+ macrophages and may serve as a circulating marker to track NAFLD progression. |
