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Hepatocytes reprogram liver macrophages involving control of TGF-β activation, influencing liver regeneration and injury

Abstract (Expand)

Background: Macrophages play an important role in maintaining liver homeostasis and regeneration. However, it is not clear to what extent the different macrophage populations of the liver differ in … terms of their activation state and which other liver cell populations may play a role in regulating the same. Methods: Reverse transcription PCR, flow cytometry, transcriptome, proteome, secretome, single cell analysis, and immunohistochemical methods were used to study changes in gene expression as well as the activation state of macrophages in vitro and in vivo under homeostatic conditions and after partial hepatectomy. Results: We show that F4/80+/CD11bhi/CD14hi macrophages of the liver are recruited in a C-C motif chemokine receptor (CCR2)–dependent manner and exhibit an activation state that differs substantially from that of the other liver macrophage populations, which can be distinguished on the basis of CD11b and CD14 expressions. Thereby, primary hepatocytes are capable of creating an environment in vitro that elicits the same specific activation state in bone marrow–derived macrophages as observed in F4/80+/CD11bhi/CD14hi liver macrophages in vivo. Subsequent analyses, including studies in mice with a myeloid cell–specific deletion of the TGF-β type II receptor, suggest that the availability of activated TGF-β and its downregulation by a hepatocyte-conditioned milieu are critical. Reduction of TGF-βRII-mediated signal transduction in myeloid cells leads to upregulation of IL-6, IL-10, and SIGLEC1 expression, a hallmark of the activation state of F4/80+/CD11bhi/CD14hi macrophages, and enhances liver regeneration. Conclusions: The availability of activated TGF-β determines the activation state of specific macrophage populations in the liver, and the observed rapid transient activation of TGF-β may represent an important regulatory mechanism in the early phase of liver regeneration in this context.

Authors: Stephanie D. Wolf, Christian Ehlting, Sophia Müller-Dott, Gereon Poschmann, Patrick Petzsch, Tobias Lautwein, Sai Wang, Barbara Helm, Marcel Schilling, Julio Saez-Rodriguez, Mihael Vucur, Kai Stühler, Karl Köhrer, Frank Tacke, Steven Dooley, Ursula Klingmüller, Tom Luedde, Johannes G. Bode

Date Published: 2023

Publication Type: Journal

Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression

Abstract (Expand)

Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male …e, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of ‘rest-and-jump genes’ that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30–48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.

Authors: Ahmed Ghallab, Maiju Myllys, Adrian Friebel, Julia Duda, Karolina Edlund, Emina Halilbasic, Mihael Vucur, Zaynab Hobloss, Lisa Brackhagen, Brigitte Begher-Tibbe, Reham Hassan, Michael Burke, Erhan Genc, Lynn Johann Frohwein, Ute Hofmann, Christian H. Holland, Daniela González, Magdalena Keller, Abdel-latif Seddek, Tahany Abbas, Elsayed S. I. Mohammed, Andreas Teufel, Timo Itzel, Sarah Metzler, Rosemarie Marchan, Cristina Cadenas, Carsten Watzl, Michael A. Nitsche, Franziska Kappenberg, Tom Luedde, Thomas Longerich, Jörg Rahnenführer, Stefan Hoehme, Michael Trauner, Jan G. Hengstler

Date Published: 1st Oct 2021

Publication Type: Journal

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