Insights into Previously Unknown Compensatory Mechanisms Found in Liver Disease

A team of researchers has uncovered a previously unknown compensatory mechanism found in liver disease. If Kupffer cells (KCs), a specific kind of immune cells found in the liver, become impaired by tissue scarring, immune cells originating in the bone marrow flow to the organ, where they form larger cell clusters to perform the same function. 

The liver is an amazing organ. It is responsible for both absorbing nutrients and breaking down toxins. Beyond that, the liver plays a lesser known but still vital role as the body’s central immunological organ. The liver is instrumental in keeping the human bloodstream free of pathogens, the liver filters out more than 90 percent of the foreign material involved.

This essential function of the organ is performed by a kind of specialized immune cell — macrophages known as Kupffer cells (KCs), which are named for German Baltic anatomist Karl Wilhelm von Kupffer. To perform their filtration function, Kupffer cells are located in the small blood vessels of the liver, the sinusoids, where they receive continuous signals from the hepatic cells themselves and those lining the blood vessels of the liver. In severe disease, especially chronic liver disease, damage to the liver causes a buildup of scar tissue known as fibrosis, which impairs the organ’s function. In the advanced stage of this tissue remodeling process, the area around the Kupffer cells also undergoes fateful changes — with consequences that were unknown until now.

A research team led by immunologist Dr. Paul Kubes, PhD partnered with colleagues at Charité to investigate this phenomenon. One of their primary aims was to improve treatment options in the future for patients with liver fibrosis.

Although there are already good models of liver disease, no one has yet been able to trace the development of liver fibrosis and the key filtration function at the same time.

Now, the international team has done just that. Using an innovative microscopy technique that makes it possible to observe cellular functions in detail in a living organism and other microscopy techniques, the researchers closely studied the functioning of Kupffer cells in the animal model and in tissue samples taken from patients with liver cirrhosis. In the process, they identified a new cell type, which they call Kupffer cell-like syncytia. These are a kind of giant cells — larger, multinucleated clusters of cells formed out of immune cells originating in the bone marrow that have traveled to the scene in response.

The newly formed KC-like syncytia take over the filtration function of the actual Kupffer cells from then on. Since they have to exist inside changed blood vessels, the immune cells that have migrated to the site adapt, forming net-like structures that turn them into an effective microbial filter. The researchers describe the molecular mechanisms 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 Kubes, the head of the study. “Previously, one school of thought was that immune cells from the bone marrow should be prevented from infiltrating the liver. But as our study shows, that could be harmful. Instead of suppressing immune function in advanced disease, it could even be a good idea to promote it.”

The study was performed at three large liver transplantation centers. It showed that the processes involved in liver fibrosis in humans are similar to those observed in the animal model. “We suspect that the liver preserves its function up to a certain level of damage by recruiting the KC-like syncytia. Ultimately, formation of scar tissue in the liver is also an evolutionarily advantageous mechanism by which a damaged organ ensures survival. So it definitely makes sense for the immune system to adapt as well,” explains Peiseler, who receives support from the Clinician Scientist Program of Charité and the Berlin Institute of Health at Charité.

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Sources:

Moritz Peiseler, Bruna Araujo David, Joel Zindel, Bas G. J. Surewaard, Woo-Yong Lee, Felix Heymann, Ysbrand Nusse, Fernanda V. S. Castanheira, Raymond Shim, Adrien Guillot, Alix Bruneau, Jawairia Atif, Catia Perciani, Christina Ohland, Priyanka Ganguli Mukherjee, Annika Niehrs, Roland Thuenauer, Marcus Altfeld, Mathias Amrein, Zhaoyuan Liu, Paul M. K. Gordon, Kathy McCoy, Justin Deniset, Sonya MacParland, Florent Ginhoux, Frank Tacke, Paul Kubes. Kupffer cell–like syncytia replenish resident macrophage function in the fibrotic liver. Science, 2023; 381 (6662) DOI: 10.1126/science.abq5202

Charité – Universitätsmedizin Berlin. “Liver fibrosis: Giant cells step in to compensate for impaired immune function.” ScienceDaily. ScienceDaily, 28 September 2023. <www.sciencedaily.com/releases/2023/09/230928151826.htm>.

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