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Macrophage functional diversity in NAFLD — more than inflammation

Abstract

Macrophages have diverse phenotypes and functions due to differences in their origin, location and pathophysiological context. Although their main role in the liver has been described as immunoregulatory and detoxifying, changes in macrophage phenotypes, diversity, dynamics and function have been reported during obesity-related complications such as non-alcoholic fatty liver disease (NAFLD). NAFLD encompasses multiple disease states from hepatic steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocarcinoma. Obesity and insulin resistance are prominent risk factors for NASH, a disease with a high worldwide prevalence and no approved treatment. In this Review, we discuss the turnover and function of liver-resident macrophages (Kupffer cells) and monocyte-derived hepatic macrophages. We examine these populations in both steady state and during NAFLD, with an emphasis on NASH. The explosion in high-throughput gene expression analysis using single-cell RNA sequencing (scRNA-seq) within the last 5 years has revolutionized the study of macrophage heterogeneity, substantially increasing our understanding of the composition and diversity of tissue macrophages, including in the liver. Here, we highlight scRNA-seq findings from the last 5 years on the diversity of liver macrophages in homeostasis and metabolic disease, and reveal hepatic macrophage function beyond their classically described inflammatory role in the progression of NAFLD and NASH pathogenesis.

Key points

  • Macrophages are highly plastic cells of the immune system that can acquire a spectrum of phenotypes according to their spatiotemporal pathophysiological context.

  • Liver macrophages are either embryo-derived resident macrophages or recruited peripheral monocyte-derived macrophages.

  • Liver macrophages have been shown to contribute to non-alcoholic fatty liver disease (NAFLD) progression in obesity through production of both inflammatory and non-inflammatory factors.

  • Single-cell RNA sequencing (scRNA-seq) has identified distinct liver macrophage subsets in mice and humans in health and liver disease.

  • scRNA-seq has enabled the identification of novel pathogenic factors expressed by liver macrophages that could exacerbate or protect from NAFLD progression.

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Fig. 1: Liver macrophage turnover in health and disease.
Fig. 2: scRNA-seq studies in mouse and human livers revealed distinct macrophage subsets.
Fig. 3: Liver macrophage depletion and obesity-associated effects in mice.
Fig. 4: Key cellular interactions between liver macrophages and other liver cell types in NAFLD and NASH.

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Acknowledgements

The authors thank R. Harris (Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, 171 76 Stockholm, Sweden) and S. Craige (Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia) for their valuable comments on the manuscript. M.A., E.B. and P.C. acknowledge the support of funds from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 864788), the EFSD supported by EFDS/Lilly European Diabetes research programme, the Karolinska Institutet, the Swedish Research Council (M.A.; 2015-03582 and 2019-01056), the Novo Nordisk Foundation (M.A.; NNF20OC0060053, NNF19OC0057127), including the Metabolite-Related Inflammation and Disease Consortium (MeRIAD; NNF0064142), and the Strategic Research Programmes in Diabetes (M.A.).

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Correspondence to Myriam Aouadi.

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Nature Reviews Endocrinology thanks Charlotte Scott, Frank Tacke and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Fate mapping

Labelling of specific cell subsets in the embryo to trace their contribution to cell populations and tissues in the adult organism.

Yolk sac

A sac attached to the embryo during development that provides nutrients and cells to the embryo.

Sterile injury

Injury or inflammation not caused by pathogenic infection.

Tissue monocytes

Cell population identified in the liver tissue by single-cell RNA sequencing (scRNA-seq) with a phenotype similar to circulating monocytes.

Scar-associated macrophages

Liver macrophages with a lipid-handling phenotype mainly associated with the development of liver fibrosis in patients with cirrhosis.

Tissue-specific enhancer

A regulatory element that induces tissue-specific transcription factors shaping the phenotype of tissue-resident cells.

Lipid-associated macrophages

Tissue macrophages with a lipid handling phenotype mainly associated with the development of obesity and non-alcoholic steatohepatitis.

Crown-like structures

Histological finding where macrophages are surrounding lipid-laden hepatocytes (in the liver) or dying adipocytes (in the adipose tissue) in a crown-like structure.

Liver non-parenchymal cells

Liver cells that do not make up the liver parenchyma including liver sinusoidal endothelial cells, hepatic stellate cells and immune cells.

Temporal trajectory analysis

In silico analysis of cell trajectories or cell differentiation patterns based on scRNA-seq data.

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Barreby, E., Chen, P. & Aouadi, M. Macrophage functional diversity in NAFLD — more than inflammation. Nat Rev Endocrinol 18, 461–472 (2022). https://doi.org/10.1038/s41574-022-00675-6

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