Immune Cell Dynamics in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Central to disease progression are dynamic changes in the hepatic immune landscape. In healthy liver, Kupffer cells maintain homeostasis by clearing pathogens and apoptotic debris. In NAFLD, lipid accumulation and hepatocyte stress trigger Kupffer cell activation, secretion of pro-inflammatory cytokines and chemokines, and a relative loss of homeostatic function. Concurrently, blood monocytes infiltrate and differentiate into monocyte-derived macrophages, adopting phenotypes that range from pro-inflammatory (M1) to pro-resolving (M2). Cross-talk between macrophages, hepatic stellate cells and other non-parenchymal cells amplifies inflammation, promotes fibrogenesis and shapes the microenvironment. Neutrophils, natural killer T cells and dendritic cells further contribute to cytokine networks and tissue remodelling. Genetic predispositions and metabolic signals modulate immune responses through pathways such as NF-κB and PPAR-γ. Understanding these interwoven processes is crucial for developing interventions that rebalance immune activation, limit fibrosis and restore hepatic function.

Research from Nature Portfolio

Studies have revealed that long-term exposure to high-fat diet skews Kupffer cells towards an M1-predominant phenotype, driving local inflammation and steatosis. Activation of PPAR-γ in these cells restores an M2-biased state, attenuates NF-κB-dependent cytokine release and alleviates liver injury, highlighting macrophage polarisation as a therapeutic target. In parallel, investigation of genetic variants in interferon-λ demonstrated that individuals harbouring a specific rs12979860 genotype exhibit heightened hepatic inflammation and accelerated fibrosis, independent of aetiology. This finding underscores the impact of host genetics on immune-mediated progression of fatty liver disease.

Immune Cell Dynamics in Non-Alcoholic Fatty Liver Disease publication trend

The graph below shows the total number of articles in immune cell dynamics in non-alcoholic fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Kupffer cells: Liver-resident macrophages that clear pathogens and maintain immune tolerance.
Monocyte-derived macrophages (Mo-macs): Infiltrating macrophages differentiated from circulating monocytes during inflammation.
M1/M2 polarization: Functional states of macrophages characterised by pro-inflammatory (M1) or anti-inflammatory/pro-resolving (M2) profiles.
Hepatic stellate cells (HSCs): Pericyte-like cells that, when activated by inflammatory mediators, produce collagen and drive fibrosis.
Lipid-associated macrophages (LAMs): A specialised macrophage subset enriched in steatotic liver, involved in lipid handling and matrix remodelling.
MyD88/NF-κB pathway: A signalling cascade downstream of Toll-like receptors that induces transcription of inflammatory genes.

References

1. Crosstalk Between Liver Macrophages and Surrounding Cells in Nonalcoholic Steatohepatitis. Frontiers in Immunology (2020).
2. Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease. Scientific Reports (2017).
3. Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease. Nature Communications (2015).
4. METTL14 downregulation drives S100A4+ monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression. Signal Transduction and Targeted Therapy (2024).
5. Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver. Immunity (2020).
6. Kuppfer Cells Trigger Nonalcoholic Steatohepatitis Development in Diet-induced Mouse Model through Tumor Necrosis Factor-α Production*. Journal of Biological Chemistry (2012).