Understanding the liver macrophage niche through intravital microscopy: Implications for disease and therapy

The liver macrophage niche plays a central role in maintaining hepatic homeostasis and driving responses to injury. Advances in intravital microscopy are providing unprecedented insights into how these cells adapt in both health and disease, opening new avenues for understanding liver pathophysiology.

In this Q&A, Future Leader Dr Moritz Peiseler (Charité Universitätsmedizin Berlin, Berlin, Germany) highlights how intravital microscopy reveals the dynamic, environment-dependent behaviour of liver macrophages, showing early disease-related changes that could guide new diagnostic and therapeutic strategies, while emphasizing the innate immune system’s memory and the potential for future human applications.

The abstract “The dynamic liver macrophage niche in health and disease: Lessons from using intravital microscopy” was presented at UEG Week, 4–7 October, Berlin, Germany.

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I’m Dr Moritz Peiseler. I’m a clinical hepatologist from the Department of Hepatology and Gastroenterology at Charity University in Berlin. I’m a liver immunologist and completed my postdoctoral training in liver immunity with Professor Paul Kubes at the University of Calgary. I also have expertise in using intravital microscopy to study immune cells.

What has intravital microscopy revealed about the dynamic behaviour of liver macrophages that other techniques could not capture?

Other techniques include well-established methods such as traditional histology, which has been used for hundreds of years, as well as emerging multi-omics techniques, such as single-cell transcriptomics. While they are great, they capture a single time-point and if you think about macrophages, they are very dynamic cells and act as a hub of immunity, interacting with a lot of cells.

When you image statically and see a cell that is adjacent to a macrophage, it could be a random bypassing or it could be an intense crosstalk, for instance, antigen presentation or phagocytosis. This is something that can only be captured when you image dynamically. Intravital imaging adds that 4th dimension, that temporal component that no other technology to date has.

How does the liver macrophage niche differ across physiological and pathological conditions?

Over the past decade, we have learned that there is a unique subset of macrophages in most bodies. During development, these macrophages enter an organ, age alongside it, and acquire a distinct genetic imprint from the environment that they serve. These macrophages come from the same progenitor cell, but become specialized with unique gene expression based on their niche. This is what drives the physiological macrophage.

What we have come to appreciate is that during any type of liver disease, the environment of the Kupffer cell (the liver resident macrophage) changes a lot. During fatty liver disease, the hepatocytes balloon and take up fat. During liver fibrosis, there is capitalization of the sinusoids (the vascular bed where the Kupffer cells live) changing the architecture. This alters signalling to the Kupffer cells, causing them to lose key functional markers and essentially forget that they are in the liver, and they differentiate to look like any other macrophage.

How could these insights translate into new diagnostic or therapeutic approaches for liver disease?

We think that macrophage changes are happening very early during disease. When we look at metabolic dysfunction-associated steatotic liver disease (MASLD), which is the most prevalent chronic liver disease, we worry when a patient develops metabolic dysfunction-associated steatohepatitis (MASH), meaning that there is inflammation. However, our basic research tells us that there are already profound changes of the macrophages even before inflammation.

We could predict, based on the macrophage changes, who will be at risk of developing more aggressive disease and who could potentially have cancer down the line. Using our intravital imaging, we have a way to specifically target these macrophages, and we could potentially revert the phenotype and the liver-related effects that come from the macrophages at an early stage.

What are the key advantages and limitations of intravital microscopy in studying immune cell behaviour in the liver?

Intravital microscopy is a dynamic tool that does not require taking cells out of their natural environment. For macrophages, when you take them out of the liver they change – they lose their shape, and they lose a lot of their gene expression. Intravital imaging really gives you the opportunity to study these cells functionally.

The limitation is that intravital imaging is not established in humans and it would be rather difficult to do so. We can use it in rodent models, zebrafish, and even chickens, but not in humans. We think the field may be heading toward using ex vivo human tissues, perfusing them in the lab, and studying immune behaviour in a more natural-like environment, though it is still somewhat artificial. There are also technological developments which could potentially make it possible to image in vivo, for instance, intraoperatively in humans.

How will the evolving understanding of the liver macrophage niche shape the future of hepatology?

We are now seeing a revolution in hepatology when it comes to metabolic liver diseases with the approval of GLP-1 agonists and resmetirom. The early data is really fascinating, and everybody is really excited to see fibrosis regression and reversion of steatosis. What we do not know is how much the immune system will also revert to normal.

Data from many human diseases suggest that the innate immune system, like the adaptive immune system, exhibits memory. We could predict that even if patients lose weight and have regression of fibrosis, they might still be more susceptible to certain immune-related events compared to those who have never been obese or had a MASLD. This is where focusing on the immune system and the macrophages will be critical.