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  • Review Article
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Hepatic inflammatory responses in liver fibrosis

Nature Reviews Gastroenterology & Hepatology volume 20, pages 633–646 (2023)Cite this article

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Abstract

Chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) or viral hepatitis are characterized by persistent inflammation and subsequent liver fibrosis. Liver fibrosis critically determines long-term morbidity (for example, cirrhosis or liver cancer) and mortality in NAFLD and nonalcoholic steatohepatitis (NASH). Inflammation represents the concerted response of various hepatic cell types to hepatocellular death and inflammatory signals, which are related to intrahepatic injury pathways or extrahepatic mediators from the gut–liver axis and the circulation. Single-cell technologies have revealed the heterogeneity of immune cell activation concerning disease states and the spatial organization within the liver, including resident and recruited macrophages, neutrophils as mediators of tissue repair, auto-aggressive features of T cells as well as various innate lymphoid cell and unconventional T cell populations. Inflammatory responses drive the activation of hepatic stellate cells (HSCs), and HSC subsets, in turn, modulate immune mechanisms via chemokines and cytokines or transdifferentiate into matrix-producing myofibroblasts. Current advances in understanding the pathogenesis of inflammation and fibrosis in the liver, mainly focused on NAFLD or NASH owing to the high unmet medical need, have led to the identification of several therapeutic targets. In this Review, we summarize the inflammatory mediators and cells in the diseased liver, fibrogenic pathways and their therapeutic implications.

Key points

  • The liver harbours a dense network of phagocytes that maintain tolerance under non-inflammatory conditions and quickly sense hepatocyte stress and injury signals leading to the activation of pro-inflammatory cascades.

  • Upon injury, leukocytes rapidly infiltrate the liver parenchyma, contributing to inflammation and fibrogenesis by producing soluble mediators that activate other immune cells and non-parenchymal cell populations.

  • Inflammatory mediators can activate hepatic stellate cells (HSCs), the main effector cells during hepatic fibrogenesis, resulting in excessive extracellular matrix deposition as a wound-healing or scarring response.

  • Production of pro-inflammatory mediators by activated HSCs, in turn, perpetuates hepatic inflammation, resulting in a chronic cycle of inflammation and formation of scar tissue, ultimately leading to organ failure.

  • Current technological advances have led to an unprecedented comprehensive understanding of the hepatic inflammatory processes underlying fibrogenesis, resulting in the identification of novel potential anti-inflammatory and antifibrotic targets.

  • Treatment of the underlying liver disease seems the most effective antifibrotic strategy, but developing efficient therapies remains challenging as preclinical results rarely translate to human disease in clinical trials.

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Fig. 1: Inflammatory processes modulating fibrogenesis.
Fig. 2: Activation and deactivation of HSCs.

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Acknowledgements

L.H. is supported by the German Research Foundation (DFG SPP2306) and the Else-Kroener-Fresenius-Stiftung (grant ID 2021_EKEA.145). F.T. is supported by the German Research Foundation (DFG SFB/TRR 296 and CRC1382, project ID 403224013) and the German Ministry of Education and Research (BMBF DEEP-HCC consortium, BMBF Immun Avatar consortium).

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  1. Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité — Universitätsmedizin Berlin, Berlin, Germany

    Linda Hammerich & Frank Tacke

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  1. Linda Hammerich
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  2. Frank Tacke
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Both authors contributed equally to all aspects of the article.

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Correspondence to Frank Tacke.

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Competing interests

F.T.’s laboratory has received research funding from Allergan, Bristol-Myers Squibb, Gilead and Inventiva (funding to the institution). F.T. has received honoraria for consulting or lectures from Astra Zeneca, Gilead, AbbVie, BMS, Boehringer, Madrigal, Intercept, Falk, Ionis, Inventiva, Merz, Pfizer, Alnylam, NGM, CSL Behring, Novo Nordisk and Novartis. L.H. declares no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks Fabio Marra and the other, anonymous, reviewers for their contribution to the peer review of this work.

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NCT02548351: https://clinicaltrials.gov/ct2/show/NCT02548351

NCT03900429: https://clinicaltrials.gov/ct2/show/NCT03900429

NCT04849728: https://clinicaltrials.gov/ct2/show/NCT04849728

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Hammerich, L., Tacke, F. Hepatic inflammatory responses in liver fibrosis. Nat Rev Gastroenterol Hepatol 20, 633–646 (2023). https://doi.org/10.1038/s41575-023-00807-x

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