Israeli and German researchers discover new immune players involved in metabolic liver disease, which is becoming more common in Western countries
It is known that people who drink excessive amounts of alcohol can seriously damage their liver. But even in those who don’t drink or hardly indulge, the liver is at risk from eating too much and being overweight.
The liver works hard to perform an entire range of activities: helping us digest food, maintaining body temperature and serving as an important checkpoint of the immune system for everything that we eat. It is inside the liver that the unique, rich and complex network of immune cells and pathways is set up to decide what is a harmless food particle, and what is a dangerous pathogen that should be neutralized and removed. The liver is therefore very sensitive to the food we consume, and sometimes a bad diet can induce a serious dysregulation of the immune activities within it.
Nonalcoholic fatty liver disease (NAFLD) is an umbrella term for a range of liver conditions affecting people who drink little to no alcohol. As the name implies, the main characteristic of NAFLD is too much fat stored in liver cells.
NAFLD is increasingly common around the world, especially in Western nations, including the US, where it is the most common form of chronic liver disease and affects about one-quarter of the population.
Some people with NAFLD can develop nonalcoholic steatohepatitis (NASH), an aggressive form of fatty liver disease, which is marked by liver inflammation and may progress to advanced scarring (cirrhosis) and liver failure. This damage is similar to the damage caused by heavy alcohol use.
NAFLD usually causes no signs and symptoms, but when it does, they may include fatigue and pain or discomfort in the upper right abdomen.
Possible signs and symptoms of NASH and advanced cirrhosis include:
abdominal swelling, enlarged blood vessels just beneath the skin’s surface, an enlarged spleen; and jaundice (yellowing of the eyes and skin).
Doctors are not sure why some fatty livers develop inflammation that progresses to cirrhosis, but both NAFLD and NASH involve overweight or obesity, insulin resistance, high blood sugar; and a high levels of fats, especially triglycerides, in the blood. This leads to the deposit of fat in the liver, and for some people, this fat acts as a toxin to liver cells, causing liver inflammation and NASH, which may lead to a buildup of scar tissue in the liver. Between five percent and 12% of people with NASH will progress to cirrhosis.
To reduce your risk of NAFLD, one should follow a healthful diet, based especially on vegetables, fruits, vegetables, whole grains and healthful fats like olive oil, canola oil, avocado and nuts. Maintain a healthy weight and exercise regularly.
In a recent study reported in the prestigious journal Nature Medicine, researchers from the Weizmann Institute of Science in Rehovot, in collaboration with colleagues from Sheba Medical Center at Tel Hashomer (near Tel Aviv) and the German Cancer Research Center (DKFZ) investigated the relationship between the liver’s immune system composition and NASH pathology.
Prof. Ido Amit and Dr. Aleksandra Deczkowska, Eyal David and Dr. Assaf Weiner and Prof. Eran Elinav´s lab at Weizmann’s immunology department headed the team that included Mathias Heikenwaelder´s lab at the DKFZ and staff at the Center for Liver Diseases at Sheba Medical Center.
They discovered that a subtype of immune cells called dendritic cells becomes activated in the liver in NASH patients and in animal models and promotes the progression of this condition. This finding could in the future help develop new treatments for NASH.
To study the immune system in NASH, the scientists kept lab mice on a diet similar to an unhealthful human diet – lacking in essential nutrients, but enriched with fat and cholesterol “junk food” – and monitored the development of NASH. To survey the global immune changes in the immune cells in the liver, they used a new technology they developed for single-cell RNA sequencing that makes possible an unbiased analysis of tens of thousands of single cells without making any assumptions about their identities.
Using this technology, the scientists found that in NASH, one subtype of dendritic cells, called type 1 (cDC1) greatly expands. To make sure that this phenomenon is related to liver disease and not to a particular diet, the researchers used six different models of obesity and unhealthy metabolic diet and found that the cDC1 count was always high when NASH was induced.
To determine whether this phenomenon is unique to animal models or is also relevant to human NASH, the researchers examined liver tissue biopsied from patients on the spectrum between non-alcoholic fatty liver disease and NASH and found that numbers of cDC1 correlated with the extent of liver pathology. The more the cDC1 counts were elevated, the greater the liver damage.
Interestingly, cDC1s were also found in higher numbers in the blood of patients with fatty liver and NASH, suggesting that NASH may alter the course of hematopoiesis – the process of blood cell production in the bone marrow – skewing it towards a higher production of dendritic cells but not other blood cells. Indeed, in the bone marrow of the mice with NASH, the immature progenitor cells that give rise to dendritic cells were indeed found to be proliferating at a higher intensity.
At this point, the researchers asked what was the role of the cDC1s in NASH and whether, if they were manipulated, what would be the effect on liver pathology. They used two independent approaches to remove the cDC1s from the system while inducing NASH and measured the consequences of cDC1 absence. In one approach, mice were genetically engineered to lack cDC1s; in the other, cDC1 infiltration to the liver was blocked using targeted therapeutic antibodies. In both cases, lowering the numbers of cDC1s correlated with an alleviation of disease pathology. Especially in mice treated with cDC1 blockers, signs of severe liver damage in the blood – assessed by blood tests – were lowered after treatment.
In a normal immune response scenario, dendritic cells – which are the major “central processing unit” of the immune system – scan organs looking for immune cues, then travel to organ-linked lymph nodes, the immune response command centers, to communicate this information to T cells, which then issue instructions to other cells involved in immune responses.
The scientists suggested that this communication pathway is important in NASH, because the cDC1s are known to specifically interact with a subtype of T cells called CD8+, which – as the scientists had shown in another collaborative study recently published in Nature – promote NASH and NASH-related liver cancer.
To check if the cDC1s indeed instruct the CD8+ cells to promote liver damage, the scientists isolated pairs of physically interacting cDC1 and T cells from mice with or without NASH. They found that in NASH, the cDC1s lead to induction of liver damage-inducing T cells that are more aggressive and inflammatory.
Overall, the cDC1s seem to be an important player in NASH. Manipulating this cell type may in the future be considered a therapeutic way of dealing with NASH and its severe consequences.
Deczkowska concluded: “We know that the immune system has a role in protecting us from pathogens, but in recent years it has been found to be involved in other diseases, including cancer, obesity, diabetes and even Alzheimer’s. The healing potential of the immune system can be harnessed for treating these diseases, instead of targeting the disease mechanisms directly. This approach, known as immunotherapy, has already led to recent breakthroughs in cancer treatment, and we believe it will soon be extended to other medical problems, such as NASH.”
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