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Lipid-Associated Macrophages Drive Liver Repair Post-Injury

A macrophage.
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New findings from the VIB-UGent Center for Inflammation Research reveal that macrophage activation states are crucial for liver repair following injury. The study, led by Prof. Charlotte Scott and her team, was published in Immunity and identifies a key role for lipid-associated macrophages (LAMs) and LAM-like Kupffer cells (KCs) in promoting recovery.


Kupffer cells (KCs)

Specialized macrophages residing in the liver, essential for maintaining tissue balance under normal conditions.

Lipid-associated macrophages (LAMs)

A subset of macrophages recruited during liver injury, involved in clearing cellular debris and promoting repair.

Liver macrophages in health and injury

Macrophages are immune cells responsible for maintaining tissue homeostasis, responding to damage and facilitating repair. In the liver, Kupffer cells dominate under healthy conditions. However, upon injury – such as that caused by obesity-induced liver damage – a distinct subset of macrophages, known as LAMs, is recruited to the site.

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The study demonstrated that these LAMs, along with Kupffer cells that adapt to exhibit LAM-like features, play a critical role in tissue repair. Contrary to earlier assumptions that Kupffer cells remain static after injury, this research shows they are highly plastic, capable of transitioning to a reparative state.

Advanced methods reveal macrophage heterogeneity

Using tools like single-cell RNA sequencing and spatial transcriptomics, the researchers explored the diversity and spatial distribution of macrophages in multiple liver injury models. They found that LAMs and LAM-like Kupffer cells consistently appeared at injury sites regardless of the type of liver damage. This suggests these cells may have therapeutic relevance across a range of liver conditions.

TREM2 gene’s role in liver repair

To understand the function of these macrophage populations, the team employed animal models to selectively delete the TREM2 gene in LAMs, LAM-like Kupffer cells, or both. Their results highlighted TREM2's critical role in clearing dying and injured liver cells. Liver repair was impaired when TREM2 was absent in both populations but was restored when it was expressed in at least one. These findings underscore TREM2's potential as a therapeutic target for preventing excessive fibrosis and promoting recovery.


TREM2 gene

A gene that encodes a receptor involved in the activation of macrophages. It plays a crucial role in the clearance of dying cells and tissue repair.

Implications for therapy

The study also revealed that LAM identity is induced by the uptake of dying cells at the injury site, offering insights into how these reparative macrophages can be generated for therapeutic use. While questions remain about the detailed mechanisms of LAM activation and function, this research provides a foundation for exploring macrophage-targeted therapies to enhance liver repair.


Reference: De Ponti FF, Bujko A, Liu Z, et al. Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair. Immunity. 2025:S1074761325000020. doi: 10.1016/j.immuni.2025.01.002


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