Macrophage Dynamics in Liver Pathophysiology

The liver hosts a complex network of macrophages comprising self-renewing resident cells (Kupffer cells) and recruited monocyte-derived macrophages. Under steady-state conditions, Kupffer cells clear pathogens and maintain immune tolerance to gut-derived antigens. Upon acute or chronic injury, circulating monocytes infiltrate the liver and differentiate into macrophages that adopt diverse activation states. Pro-inflammatory phenotypes amplify hepatocellular damage through cytokine release and reactive oxygen species, whereas pro-resolution macrophages promote tissue repair via efferocytosis and production of matrix-remodelling enzymes. The plasticity of hepatic macrophages hinges on local cues—such as chemokines, growth factors and extracellular matrix components—and determines outcomes in acute liver failure, fibrogenesis, metabolic steatohepatitis and tumour surveillance. Therapeutic strategies now aim to rebalance macrophage subsets or block their recruitment to mitigate fibrosis and enhance regeneration, underscoring their central role in both disease progression and recovery.

Research from Nature Portfolio

Investigations into Notch signalling have revealed its pivotal role in coordinating hepatic stellate-cell activation and macrophage polarisation. In fibrotic livers, elevated expression of Notch pathway components drives both myofibroblast differentiation and pro-inflammatory M1 macrophage states. Pharmacological inhibition of γ-secretase suppresses TGF-β-induced stellate-cell contraction and shifts macrophages towards an anti-inflammatory phenotype, resulting in marked attenuation of collagen deposition in experimental models. This work highlights Notch as a dual regulator of stromal and immune compartments and offers a foundation for targeting cell–cell crosstalk in liver fibrosis.

Macrophage Dynamics in Liver Pathophysiology publication trend

The graph below shows the total number of articles in macrophage dynamics in liver pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Kupffer cell: Resident macrophage lining the liver sinusoid responsible for clearance of pathogens and cellular debris.

Hepatic stellate cell (HSC): Perisinusoidal cell that transforms into a collagen-producing myofibroblast during liver injury.

Macrophage polarization: Functional differentiation of macrophages into pro-inflammatory (M1) or pro-resolution (M2) phenotypes in response to microenvironmental signals.

C-C motif chemokine receptor 2 (CCR2): Cell-surface receptor guiding recruitment of monocyte-derived macrophages to sites of inflammation.

GPR65: Proton-sensing G protein-coupled receptor that modulates macrophage activation in acidic inflammatory environments.

References

1. The interplay of the Notch signaling in hepatic stellate cells and macrophages determines the fate of liver fibrogenesis. Scientific Reports (2015).
2. Targeting GPR65 alleviates hepatic inflammation and fibrosis by suppressing the JNK and NF-κB pathways. Military Medical Research (2023).
3. A Genetically Engineered Biomimetic Nanodecoy for the Treatment of Liver Fibrosis. Advanced Science (2024).
4. Macrophage Polarization and Its Role in Liver Disease. Frontiers in Immunology (2021).