Macrophage-stellate metabolic cross-talk in hepatic fibrosis

In this sub-project, we aim to analyze how metabolites produced by hepatic macrophage subsets impact hepatic stellate cell (HSC) activation in the context of metabolic dysfunction-associated steatohepatitis (MASH). MASH as the most severe form of metabolic dysfunction-associated fatty liver disease (MAFLD), is a major public health problem. It is characterized by hepatic steatosis, hepatocellular damage/death, inflammation, and varying fibrosis degree. Fibrosis results from excessive collagen and extracellular matrix (ECM) deposition by activated HSCs following hepatocyte injury. Although MASH is linked to hepatic macrophage remodeling, death of resident Kupffer cells (KC) and their replacement by diverse monocyte-derived macrophage populations, how metabolites produced by these macrophage subsets impact HSC activation remains poorly understood.

Using mouse models closely mimicking human MASH and toxin-induced fibrosis models, we will isolate different MASH hepatic macrophage subsets and elucidate unique and shared metabolic/transcriptional features between them. To evaluate their influence on HSCs, we will utilize a two-pronged approach. This encompasses co-culture of the different hepatic macrophages or conditioned media from them with HSCs and in situ macrophage metabolic characterization of them, determining their proximity to HSCs, collagen, and regions of cell death (with A Haschemi/A Miller). Contributions of adipose derived lipids, microbiome and intestinal permeability, all of which play a crucial in MASH pathogenesis, to the immuno-metabolic profile of MASH macrophages and their influence on HSCs, will be evaluated (together with M. Schweiger, C. Moissl-Eichinger, T. Weichhart).

Overall, we expect to provide evidence that in obesity different liver macrophage populations immuno-metabolically promote or resolve fibrosis and determine how this is linked to cell death. Identification of such metabolites and their immuno-modulatory effect on HSCs is expected to have broad implications as it may identify novel metabolic avenues to alter macrophage-HSC cross-talk and hence modulate hepatic fibrogenesis, for which there are no effective therapies.

Omar Sharif

Medical University of Vienna
Center for Physiology and Pharmacology
Institute for Vascular Biology and Thrombosis Research
Schwarzspanierstrasse 17
1090 Vienna

omar.sharif@meduniwien.ac.at
Sharif Lab

Project Members

Anja Dobrijevic
PhD Student
SFB Member

Alona Agirre-lizaso

Postdoctoral Researcher
SFB affiliated

Research Publications

Vogel A, Martin K, Soukup K, Halfmann A, Kerndl M, Brunner JS, Hofmann M, Oberbichler L, Korosec A, Kuttke M, Datler H, Kieler M, Musiejovsky L, Dohnal A*, Sharif O*, Schabbauer G*(2022). JAK1 signaling in dendritic cells promotes peripheral tolerance in autoimmunity through PD-L1 mediated regulatory T cell induction. Cell Reports Feb 22;38(8):110420; https://doi.org/10.1016/j.celrep.2022.110420

Sharif O, Brunner JS, Korosec A, Martins R, Jais A, Snijder B, Vogel A, Caldera M, Hladik A, Lakovits K, Saluzzo S, Boehm B, Gorki AD, Mesteri I, Lindroos JC, Tillmann K, Stoiber D, Menche J, Schabbauer G, Bilban M, Superti-Furga G, Esterbauer H, Knapp S (2021). Beneficial Metabolic Effects of TREM2 in Obesity are Uncoupled from its Expression on Macrophages. Diabetes Feb 24. https://doi.org/10.2337/db20-0572

Brunner JS, Vogel A, Lercher A, Caldera M, Korosec A, Pühringer M, Hofmann M, Hajto A, Kieler M, Garrido LQ, Kerndl M, Kuttke M, Mesteri I, Górna MW, Kulik M, Dominiak PM, Brandon AE, Estevez E, Egan CL, Gruber F, Schweiger M, Menche J, Bergthaler A, Weichhart T, Klavins K, Febbraio MA, Sharif O*, Schabbauer G* (2020). The PI3K pathway preserves metabolic health through MARCO-dependent lipid uptake by adipose tissue macrophages. Nature Metabolism Dec;2(12):1427-1442. https://doi.org/10.1038/s42255-020-00311-5

Esparza-Baquer A, Labiano I, Sharif O, Agirre AL 1, Oakley F, Rodrigues PM, Zhuravleva E, O'Rourke CJ, Hijona E, Agüero RJ, Riaño I, Landa A, Casta AL, Zaki MYW, Munoz-Garrido P, Azkargorta M, Elortza F, Vogel A, Schabbauer G, Aspichueta P, Andersen JB, Knapp S, Mann DA, Bujanda L, Banales JM, Perugorria MJ (2020). TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms. Gut Sep 9;gutjnl-2019-319227. https://doi.org/10.1136/gutjnl-2019-319227

Perugorria MJ, Esparza-Baquer A, Oakley F, Labiano I, Korosec A, Jais A, Mann J, Tiniakos D, Santos-Laso A, Arbelaiz A, Gawish R, Sampedro A, Fontanellas A, Hijona E, Jiménez-Agüero R, Esterbauer H, Stoiber D, Bujanda L, Banales JM, Knapp S, Sharif O*, Mann DA* (2018) Non-Parenchymal TREM-2 protects the Liver from Immune-mediated Hepatocellular damage. Gut Jan 27. https://doi.org/10.1136/gutjnl-2017-314107

Jais A, Einwallner E, Sharif O, Gossens K, Lu TT, Soyal SM, Medgyesi D, Neureiter D, Paier-Pourani J, Dalgaard K, Duvigneau JC, Lindroos J, Zapf T, Amann S, Saluzzo S, Jantscher F, Stiedl P, Todoric J, Martins R, Oberkofler H, Müller S, Hauser-Kronberger C, Kenner L, Casanova E, Sutterlüty-Fall H, Bilban M, Miller K, Kozlov A, Krempler F, Knapp S, Lumeng CN, Patsch W, Wagner O, Pospisilik AJ, Esterbauer H (2014). Heme Oxygenase-1 Drives Metaflammation and Insulin Resistance in Mouse and Man. Cell Jul 3;158(1):25-40. https://doi.org/10.1016/j.cell.2014.04.043

Sharif O, Gawish R, Warszawska JM, Martins R, Lakovits K, Hladik A, Doninger B, Brunner J, Korosec A, Schwarzenbacher EJ, Berg T, Kralovics R, Colinge J, Mesteri I, Gilfillan S, Salmaggi A, Verschoor A, Colonna M, Knapp S (2014). The Triggering receptor expressed on myeloid cells 2 inhibits complement component 1q effector mechanisms and exerts detrimental effects during pneumococcal pneumonia. Plos Pathogens Jun 12;10(6) e1004167. https://doi.org/10.1371/journal.ppat.1004167

Matt U*, Sharif O*, Martins R, Furtner T, Langeberg L, Gawish R, Elbau I, Zivkovic A, Lakovits K, Oskolkova O, Doninger B, Vychytil A, Perkmann T, Schabbauer G, Binder CJ, Bochkov VN, Scott JD, Knapp S. (2013). WAVE1 mediates suppression of phagocytosis by phospholipid-derived DAMPs. J Clin Invest 123(7):3014-24. https://doi.org/10.1172/JCI60681

Sharif O, Matt U, Saluzzo S, Lakovits K, Haslinger I, Furtner T, Doninger B, Knapp S (2013). The scavenger receptor CD36 downmodulates the early inflammatory response while enhancing bacterial phagocytosis during pneumococcal pneumonia. J Immunol 190(11):5640-8. https://doi.org/10.4049/jimmunol.1202270

Baumann CL*, Aspalter IM*, Sharif O*, Pichlmair A, Blüml S, Grebien F, Bruckner M, Pasierbek P, Aumayr K, Planyavsky M, Bennett KL, Colinge J, Knapp S#, Superti-Furga G (2010). CD14 is a coreceptor of Toll-like receptors 7 and 9. J Exp Med. 207(12):2689-701. https://doi.org/10.1084/jem.20101111