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Regulation and functional roles of chemokines in liver diseases

Abstract

Inflammation is a major contributor to the pathogenesis of almost all liver diseases. Low-molecular-weight proteins called chemokines are the main drivers of liver infiltration by immune cells such as macrophages, neutrophils and others during an inflammatory response. During the past 25 years, tremendous progress has been made in understanding the regulation and functions of chemokines in the liver. This Review summarizes three main aspects of the latest advances in the study of chemokine function in liver diseases. First, we provide an overview of chemokine biology, with a particular focus on the genetic and epigenetic regulation of chemokine transcription as well as on the cell type-specific production of chemokines by liver cells and liver-associated immune cells. Second, we highlight the functional roles of chemokines in liver homeostasis and their involvement in progression to disease in both human and animal models. Third, we discuss the therapeutic opportunities targeting chemokine production and signalling in the treatment of liver diseases, such as alcohol-associated liver disease and nonalcoholic steatohepatitis, including the relevant preclinical studies and ongoing clinical trials.

Key points

  • Chemokines are secreted mediators that regulate the infiltration of immune cells into the liver and modulate the activation and proliferation of almost all liver cell types.

  • Individual chemokines can interact with their corresponding receptors based on their structural characteristics and local context and can contribute to liver homeostasis by interacting with immune and non-immune liver cells.

  • Tumour necrosis factor (TNF), IL-6 and many other cytokines can rapidly stimulate the transcription of pro-inflammatory chemokines in a robust and co-regulated manner through the epigenetically primed chromatin 3D conformation of enhancer–promoter interactions.

  • Chemokines are associated with liver disease and it is critical to identify different major players that provide the similarities and dissimilarities between mouse and human genomic arrangement.

  • Current drug development based on chemokines and receptors in liver diseases is limited and can be greatly improved with novel therapeutic strategies.

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Fig. 1: Chemokine pathways in liver homeostasis and inflammation.
Fig. 2: Chemokines in the pathogenesis of alcohol-related injury.
Fig. 3: Chemokine actions in HCC.

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Acknowledgements

Work on chemokines in the laboratory of V.H.S. is supported by NIH grants AA21171 and DK59615.

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V.H.S. and S.C. discussed and determined content for the article. V.H.S. made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission. S.C. researched data for the article, made a substantial contribution to discussion of content, wrote the article and reviewed/edited the manuscript before submission. M.L. and T.S.S. researched data for the article and wrote the article.

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Correspondence to Sheng Cao or Vijay H. Shah.

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FANTOM5 database: https://fantom.gsc.riken.jp/zenbu/gLyphs/#config=2Z4giXeUDRQulVO5sw_x8C;loc=hg19::chr4:74734631..74737497

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Cao, S., Liu, M., Sehrawat, T.S. et al. Regulation and functional roles of chemokines in liver diseases. Nat Rev Gastroenterol Hepatol (2021). https://doi.org/10.1038/s41575-021-00444-2

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