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Immune cell-mediated features of non-alcoholic steatohepatitis

Nature Reviews Immunology volume 22, pages 429–443 (2022)Cite this article

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Abstract

Non-alcoholic fatty liver disease (NAFLD) includes a range of hepatic manifestations, starting with liver steatosis and potentially evolving towards non-alcoholic steatohepatitis (NASH), cirrhosis or even hepatocellular carcinoma. NAFLD is a major health burden, and its incidence is increasing worldwide. Although it is primarily a disease of disturbed metabolism, NAFLD involves several immune cell-mediated inflammatory processes, particularly when reaching the stage of NASH, at which point inflammation becomes integral to the progression of the disease. The hepatic immune cell landscape is diverse at steady state and it further evolves during NASH with direct consequences for disease severity. In this Review, we discuss current concepts related to the role of immune cells in the onset and progression of NASH. A better understanding of the mechanisms by which immune cells contribute to NASH pathogenesis should aid the design of innovative drugs to target NASH, for which current therapeutic options are limited.

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Fig. 1: Contributing factors in NAFLD progression and NASH pathogenesis.
Fig. 2: Immune landscape of the healthy liver.
Fig. 3: Immune modulation of NASH pathogenesis.
Fig. 4: The diversity of hepatic macrophages during NASH.

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Acknowledgements

The authors apologize to colleagues whose work could not be cited owing to space limitations. This work was supported by Inserm, Sorbonne Université and grants from the Fondation de France (project number 00056835), the Agence Nationale pour la Recherche (ANR-15-CE14-0015-02, ANR-17-CE14-0009-02, ANR-17-CE14-0023-01 and ANR-20-CE15-0018-02) and the city of Paris (Emergence-s- program) to E.L.G. as well as grants from the Fondation de France (project number 00096295), Alliance Sorbonne Université (Programme Emergence) and the Agence Nationale pour la Recherche (ANR-17-CE14-0044-01) to T.H. The authors thank G. Marcelin for critical reading of the manuscript.

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    Thierry Huby & Emmanuel L. Gautier

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Glossary

Insulin resistance

A state in which cells are not able to respond fully to insulin or induce signalling pathways downstream of the insulin receptor.

Steatosis

Describes the abnormal accumulation of lipids in a tissue.

Metabolic syndrome

A group of five conditions (increased blood pressure, high blood sugar level, excess body fat around the waist, and abnormal cholesterol or triglyceride levels) that can occur together and increase the risk of heart disease, stroke and type 2 diabetes.

Endoplasmic reticulum stress

A state of cellular stress that occurs when protein folding in the ER is impaired, leading to the accumulation of unfolded and/or misfolded proteins.

β-oxidation

Catabolic process occurring in the mitochondria by which fatty acids are converted into acetyl-CoA, a major metabolic intermediate.

Mallory–Denk bodies

Cytoplasmic aggregates of damaged cytoskeletal components found in hepatocytes during NASH or alcoholic liver disease.

Portal tracts

Areas of the liver, also known as portal triads, that consist of a bile duct, a small branch of the portal vein and a branch of the hepatic artery.

Gut-associated lymphoid tissue

Intestinal lymphoid structures, including Peyer’s patches and isolated lymphoid follicles, that are particularly rich in antibody-producing plasma cells.

Hepatic stellate cells

(HSCs). Mesenchymal liver cells found in the area between sinusoids and hepatocytes, known as the space of Disse.

Neutrophil extracellular traps

(NETs). Structures released by neutrophils that are primarily composed of a scaffold of chromatin fibres and antimicrobial proteins.

Peroxisome proliferator-activated receptor

(PPAR). Part of a group of ligand-controlled transcription factors of the nuclear receptor family that have major regulatory roles in controlling metabolic functions as well as anti-inflammatory properties.

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Huby, T., Gautier, E.L. Immune cell-mediated features of non-alcoholic steatohepatitis. Nat Rev Immunol 22, 429–443 (2022). https://doi.org/10.1038/s41577-021-00639-3

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