Our liver is home to an array of specialized immune cells that play essential roles in its immune response, tissue maintenance, and repair after injury. One group of these cells, macrophages, stands out for their crucial role in maintaining tissue homeostasis, responding to damage, and promoting healing. In recent research conducted by Prof. Charlotte Scott and her team at the VIB-UGent Center for Inflammation Research, new insights have emerged regarding the behavior of macrophages, particularly in the context of liver injury. The findings suggest that a specific activation state of a subset of these cells is essential for liver repair. These findings offer promising therapeutic implications for a range of liver diseases.
The newly published work appears in the prestigious journal Immunity and focuses specifically on macrophages in the liver. These cells, found throughout the body, have long been known for their role in cleaning up cellular debris, responding to pathogens, and promoting tissue healing following injury. In the liver, the most abundant type of macrophages are called Kupffer cells (KCs), and they play a crucial role in maintaining liver homeostasis and managing immune responses.
A New Group of Macrophages: Lipid-Associated Macrophages (LAMs)
When the liver experiences damage, such as from conditions like obesity, the body recruits another subset of macrophages known as lipid-associated macrophages (LAMs). While the role of KCs in normal liver function has been well-established, the role of LAMs in liver injury has remained somewhat unclear.
This question became the focal point of Prof. Scott’s team, who wanted to understand whether KCs alone adapt to promote healing during liver injury or if LAMs play a more significant role in the repair process.
Using a range of advanced methodologies, including single-cell RNA sequencing and spatial transcriptomics, the team examined the molecular and cellular landscape of the liver following injury. Their research revealed that both LAMs and LAM-like KCs (Kupffer cells that adopt traits similar to LAMs after injury) are vital for tissue repair following liver injury. This critical insight revealed that the LAM phenotype of macrophages is required for effective tissue recovery, even though both the KCs and LAMs contribute to repair.
As a result, this study indicates that KCs, typically considered stable resident macrophages, undergo functional adaptation post-injury, which allows them to take on characteristics of LAMs in response to the liver’s microenvironment. In other words, KCs don’t remain static after injury, as had been previously assumed; instead, they exhibit a high degree of plasticity, reshaping their function to aid the liver’s healing.
Understanding the Mechanism: TREM2 and Tissue Repair
The research team went further to investigate the specific functional contributions of these macrophage subtypes in tissue repair. Using animal models, the team selectively deleted genes in LAMs, LAM-like KCs, or both subsets of macrophages to determine their roles in tissue recovery after liver injury.
This aspect of the study identified the importance of a specific gene, Trem2, in the macrophages involved in the repair process. TREM2, a receptor involved in the uptake and clearance of dead and damaged cells, was found to be critical in at least one of the macrophage populations—LAMs or LAM-like KCs—for successful liver repair.
The researchers observed that when TREM2 was deleted from both macrophage subsets, tissue repair was compromised, and the liver exhibited signs of excessive fibrosis—a common hallmark of chronic liver injury. Conversely, when TREM2 was maintained in either the LAMs or the LAM-like KCs, the liver showed a greater capacity for recovery. This suggests that the presence of TREM2 in these cells is critical for promoting effective tissue repair and controlling the progression of liver fibrosis.
The loss of TREM2 in both macrophage populations led to delayed or failed tissue repair, implying that this molecule plays a major role in preventing complications that could result in chronic liver damage. This is an important finding since fibrosis and persistent inflammation in the liver can progress to more severe conditions like cirrhosis or even liver failure.
Activation of Macrophages and Cell Clearance
Prof. Scott’s research team also uncovered important new insights into the activation mechanisms of these macrophage populations. Specifically, it was found that the LAM identity in these cells was induced when they took on the task of phagocytosing (engulfing) and clearing dying and injured cells at the site of liver injury.
The process of clearing dead or damaged cells, known as cellular debris clearance, is fundamental for tissue repair, as it prevents further inflammation and supports tissue regeneration. The research demonstrated that LAM-like macrophages adopt their specialized phenotype after taking part in this clearing process, suggesting that this activation mechanism is not merely a response to injury but also a way for macrophages to sustain the reparative process over time.
The study’s findings thus point to the plasticity of macrophages as a key element in the liver’s ability to respond to injury. The cells are not pre-programmed to remain static or follow a fixed function; instead, they can respond flexibly to damage, adopting new roles and characteristics to support recovery. This plasticity could explain why LAM-like KCs and other macrophage subsets are involved in different injury settings across various types of liver diseases.
Therapeutic Implications: Targeting Macrophages for Liver Repair
The potential therapeutic implications of these findings are profound. Macrophages, and particularly their newly identified LAM-like state, could become essential targets for treatments aimed at improving liver repair. The concept of harnessing the body’s own immune system to address liver injuries and diseases marks an exciting step forward in treatment possibilities for chronic liver conditions such as fatty liver disease, cirrhosis, hepatitis, and even liver cancer.
Since the study identifies key molecular factors such as TREM2, which regulate macrophage functions during liver repair, modulating these factors could provide a means of guiding macrophages toward a repair-promoting phenotype. By boosting the presence of macrophages that help in cellular cleanup and tissue regeneration, researchers may be able to develop regenerative therapies that could reverse damage caused by liver disease and prevent complications such as fibrosis from worsening.
The research also provides insight into a novel way of thinking about macrophage-based therapies. Instead of simply suppressing inflammation (as is often the focus in many existing therapeutic strategies), the goal could be to guide macrophages toward promoting recovery and tissue healing. Identifying molecular pathways and regulatory genes, such as TREM2, that are involved in this process would be key to creating these new strategies.
Conclusion
This groundbreaking work by Prof. Scott and her team not only sheds new light on the complex behavior of liver macrophages but also opens up avenues for the development of novel therapies aimed at liver diseases. The team’s work shows that macrophages exhibit heterogeneity and plasticity, and these traits are crucial for their role in tissue repair.
In the case of liver injury, it is not just the presence of macrophages but their state of activation, such as the LAM-like phenotype, that determines their ability to contribute to effective tissue regeneration. The activation of these macrophages in response to dying cells is a critical step in the repair process, making TREM2 a potential therapeutic target for promoting healing and limiting the damaging effects of fibrosis.
This research is a significant step towards advancing our understanding of liver injury and repair. As we learn more about the underlying mechanisms at play in liver diseases and recovery, these findings bring us closer to developing new and more effective strategies for treating a range of liver conditions, offering hope for millions of patients worldwide.
Reference: Federico F. De Ponti et al, Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair, Immunity (2025). DOI: 10.1016/j.immuni.2025.01.002