Liver fibrosis: Giant cells step in when immune function fails

Researchers from Charité and the University of Calgary discover new type of cells

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Berlin, 28.09.2023

It is a compensatory mechanism of the diseased liver and it was previously unknown: If immune cells in the liver, the Kupffer cells, lose their function due to scarring of the tissue, immune cells from the bone marrow flood into the organ and form larger cell clusters to take over their tasks. Scientists from Charité – Universitätsmedizin Berlin and the Faculty of Medicine at the University of Calgary were able to observe for the first time how the damaged liver maintains its bacterial filter function. Their fundamental findings have been published in the journal Science* and may contribute to the development of new therapies for liver damage.

The liver is an amazing organ. It is the central metabolic organ of the body and is responsible for both the absorption of nutrients and the breakdown of toxins. It regulates fat and sugar metabolism, mineral, vitamin and hormone balance. It is able to regenerate itself. And: less known, but vital, is its role as a central immunological organ. The liver plays a major role in keeping our bloodstream free of pathogens, bacteria, viruses or fungi. If sepsis, commonly known as blood poisoning, occurs, over 90 percent of the invaders are filtered out by the liver.

This essential service of the organ is provided by a specialised defence cell – an eating cell called Kupffer cell, named after the German-Baltic anatomist Karl Wilhelm von Kupffer. To fulfil their filtering function, Kupffer cells sit in the small blood vessels of the liver, the sinusoids, and constantly receive signals from liver cells and cells lining the blood vessels of the liver. In severe diseases, most notably chronic liver disease, damage to the liver leads to an accumulation of scar tissue, fibrosis, which limits the functions of the organ. In the advanced stage of this tissue remodelling, the environment of the Kupffer cells also undergoes fatal changes – the consequences of which were previously unknown.

A research team led by immunologist Prof. Dr. Paul Kubes at the Cumming School of Medicine at the University of Calgary, together with colleagues at the Charité, has been investigating this phenomenon, not least in order to be able to better treat patients with a fibrotic liver in the future. Chronic liver diseases are on the rise worldwide. In Germany, heavy alcohol consumption and fatty liver disease in particular lead to liver fibrosis and its final stage, liver cirrhosis. According to estimates, fatty liver already affects one in four people and is caused by lifestyle habits such as overeating and lack of exercise as well as diseases such as diabetes and lipometabolic disorders. Infections or genetic causes can also lead to liver fibrosis. Although there are already good models for liver diseases, no one has yet been able to show the progression of liver fibrosis and the central filter function during it.

Role of the immune system in liver fibrosis in a new light

This is exactly what the international team has now succeeded in doing. Using a new microscopy technique that allows detailed observation of cellular functions in the living organism, as well as other microscopy techniques, the researchers have thoroughly investigated the function of Kupffer cells in animal models and in tissue samples from patients with liver cirrhosis. In the process, they were able to identify a new cell type, which they call Kupffer cell-like syncytia. These are a type of giant cells – larger, multinucleated cell clusters that have emerged from immune cells in the bone marrow.

Dr. Moritz Peiseler, scientist and doctor at the Clinic for Hepatology and Gastroenterology at the Charité and first author of the study, describes what happens in the liver in the course of scarring remodelling: “More and more liver cells die. Connective tissue forms throughout the organ and around the small blood vessels. The blood is diverted to new, enlarged vessels inside and outside the liver. As a result, the Kupffer cells lose contact with their environment and eventually no longer behave as if they were in the liver. They lose their function, no longer catch bacteria from the blood and infections of the bloodstream increase. But quite quickly, specialised monocytes, immune cells from the bone marrow, infiltrate the liver. They follow the bypass vessels and form clusters large enough to trap bacteria in the slightly larger vessels.” A life-saving compensation triggered by the microbiome, presumably the gut microbiome.

The Kupffer cell-like structures henceforth take over the filter function of the actual Kupffer cells. Since they have to exist in modified blood vessels, the immigrated immune cells adapt. They form net-like structures and thus become an effective microbial filter. The researchers were able to describe which molecular mechanisms are involved in these processes in their work. “These findings change the way we think about the role of the immune system in liver fibrosis,” says study leader Prof. Kubes. “For example, it has sometimes been thought that immune cells from the bone marrow should be prevented from entering the liver. However, as our study shows, this could be exactly what is harmful. Instead of suppressing immune function in advanced disease, it might even be a good idea to promote it.”

Basis for novel therapies and treatment of liver fibrosis

The study was conducted at three major liver transplant centres, including the Charité, and showed that the processes involved in liver fibrosis in humans are similar to those observed in animal models. Therefore, the findings raise fundamental questions for the treatment of patients with fibrotic liver. One of the main reasons why patients with cirrhosis die is infection. At the same time, many patients suffer from partly advanced liver scarring without having an increased risk of infection. “We suspect that the liver maintains its function up to a certain degree of damage by recruiting Kupffer cell-like syncytia. Ultimately, after all, liver scarring is also an evolutionarily advantageous mechanism by which a damaged organ ensures survival. Therefore, it makes perfect sense that the immune system also adapts,” explains Dr Peiseler, who is supported by the Clinician Scientist Programme of the Charité and the Berlin Institute of Health at the Charité (BIH), among others.

The current study contributes to a better understanding of how the body’s most important microbial filter functions in the development of liver diseases – a basis for developing novel therapies. The original Kupffer cells no longer behave like immune cells of the liver due to the lack of contact with the environment. It would therefore be conceivable to prevent their loss of identity and thus their loss of function. It is also now known how the liver reacts to pathological changes. Promoting this process could protect patients. Improved microbial filter function reduces the risk of dying from liver cirrhosis and can delay the need for liver transplantation, currently the only treatment option.

*Peiseler M et al. Kupffer cell-like syncytia replenish resident macrophage function in the fibrotic liver. Science 2023 Sep 08. doi: 10.1126/science.abq5202

About the study

The research was made possible by the German Research Foundation (DFG), the Charité BIH Clinician Scientist Program, the Swiss National Science Foundation (SNF), the Canadian Institute of Health Research (CIHR) and the Canada Research Chairs Program, among others.

Image: Kupffer cell-like clusters or giant cells take over the function of Kupffer cells. They are clusters of multiple cells that form mesh-like filters with high capacity in the bypass vessels. © Charité | Moritz Peiseler