July 2023 - Tim Hendrikx

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Dr. Tim Hendrikx

MedUni Wien RESEARCHER OF THE MONTH July 2023

The pathogenesis of non-alcoholic fatty liver disease, especially advanced steatohepatitis (NASH), is associated with profound changes in immune cells in the liver. Recently, the increased accumulation of a subtype of macrophages that express high levels of the receptor TREM2 has been described in fatty liver disease. Yet, the exact role of TREM2-positive macrophages in NASH was hitherto unknown. In this study, we demonstrate that TREM2-expressing macrophages are recruited to the liver where they fulfil an important protective function in NASH-related fibrosis - a precursor to liver cirrhosis. Spatial transcriptomics revealed that TREM2+ macrophages are increasingly present at areas of lipid-induced cell damage and fibrosis in the injured liver. Moreover, using bone marrow transplantation models and single-cell RNA sequencing, we found that haematopoietic TREM2 deficiency prevents efficient fat storage and breakdown of excess connective tissue, leading to increased steatohepatitis, cell death and fibrosis. These data suggest that enhancing TREM2 might be a promising target to improve therapy options. Moreover, we discovered that soluble TREM2 levels are a useful marker for determining the current status of liver disease in patients and can distinguish between the different stages of NAFLD better than markers used in clinical practice.

Selected Literature

1. T Hendrikx*, F Porsch*, MG Kiss, D Rajcic, N Papac-Miličević, C Hoebinger, L Göderle, A Hladik, LE Shaw, H Horstmann, S Knapp, S Derdak, M Bilban, L Heintz, M Krawczyk, R Paternostro, M Trauner, M Farlik, D Wolf, CJ Binder. Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH. J of Hepatology 2022 Nov;77(5):1373-1385.

2. T Hendrikx, S Lang, D Rajcic, Y Wang, S McArdle, K Kim, Z Mikulski, B Schnabl. Hepatic pIgR-mediated secretion of IgA limits bacterial translocation and prevents ethanol-induced liver disease in mice. Gut 2023 Jan 23;gutjnl-2022-328265.

3. T Hendrikx, Y Duan, Y Wang, JH Oh, LM Alexander, W Huang, P Stärkel, SB Ho, B Gao, O Fiehn, P Emond, H Sokol, JP van Pijkeren, B Schnabl. Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice. Gut. 2019 Aug;68(8):1504-1515.

4. C JL Busch*, T Hendrikx*, D Weismann, S Jackel, S MA Walenbergh, A F Rendeiro, J Weisser, F Puhm, A Hladik, L Goderle, N Papac-Milicevic, G Haas, V Millischer, S Subramaniam, S Knapp, K L Bennett, C Bock, C Reinhardt, R Shiri-Sverdlov, C J Binder. Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice. Hepatology, 2016 Dec 16