Cirrhosis is the last evolutionary stage of fibrosis associated with chronic liver disease. It affects 200,000 to 500,000 individuals in France and is responsible for 170,000 deaths per year in Europe. © Adobe Stock
Chronic liver diseases are characterized by persistent inflammation which contributes to their progression to more severe stages. They can progress to fibrosis and cirrhosis, and then require a liver transplant. Limiting the progression of fibrosis and making it regress is therefore an important therapeutic issue. Several studies have recently suggested that targeting the inflammatory response might be an interesting approach. In new work, scientists from Inserm and Université Paris-Cité in Inflammation Research Center (CRI), in collaboration with teams from AP-HP[1], have shown that blocking the activation of a particular population of T lymphocytes, the mucosa-associated lymphocytes (MAIT), might make it possible to stop the progression of fibrosis and even to make it regress. Targeting MAIT cells, which are involved in the inflammation observed in fibrosis and cirrhosis, would thus open up new perspectives for better therapeutic management of patients. This study is published in the revue Nature Communications.
Mainly of alcoholic, viral or metabolic origin, cirrhosis constitutes the last evolutionary stage of fibrosis associated with chronic liver diseases. It affects 200,000 to 500,000 individuals in France and is responsible for 170,000 deaths per year in Europe. Eventually, it leads to liver failure, the only curative treatment for which is transplantation.
A hallmark of chronic liver disease is persistent inflammation that contributes to their progression to more severe stages, including progression to fibrosis and its ultimate stage, cirrhosis. Better understanding how to regulate this inflammatory response is therefore an important issue for developing new therapeutic strategies once morest these pathologies.
In 2018, the team of Inserm researcher Sophie Lotersztajn showed that a population of T lymphocytes called MAIT promotes the progression of liver fibrosis. These immune cells are particularly abundant in the human liver and are involved in the inflammatory processes associated with fibrosis.
In their new study, the scientist and her colleagues worked with liver samples from cirrhotic patients as well as mouse models of the disease.
They showed that the administration of a pharmacological agent that inhibits the activation of MAIT cells makes it possible to limit hepatic inflammation and not only to stop the progression of fibrosis, but also to cause it to regress.
It is now well known that other immune cells, such as macrophages, play a central role in the progression and regression of fibrosis. Here, the analysis of the mechanisms involved has made it possible to show that blocking the activation of MAIT cells interrupts their dialogue with “pro-fibrogenic” macrophages, i.e. accelerators of fibrosis, and promotes the emergence of fibrosis-resolving macrophages.
In the first image, MAIT cells (in red, denoted by arrows) are localized near fibrogenic cells (in green) in the liver of cirrhotic patients. In the second image, MAIT cells (in red) are activated (activation marker in green) in the liver of cirrhotic patients. This activation is blocked in the presence of an inhibitor of MAIT cells. © Sophie Lotersztajn
“Cirrhosis is a major public health problem. While the only treatment is liver transplantation, our work opens up other therapeutic avenues to target inflammation and succeed in stopping, or even reversing, fibrosis. We must now continue research, in particular to develop drug candidates targeting and inhibiting MAITs”, concludes Sophie Lotersztajn.
[1] This work is the result of a collaboration between the team of Drs Sophie Lotersztajn and Hélène Gilgenkrantz, (Inserm-Université Paris Cité inflammation research center (CRI), the team of Dr Valérie Paradis at the CRI (also Beaujon Hospital pathology department), the anesthesia-resuscitation department (Pr Emmanuel Weiss), the teams from the Institut Curie (Dr Olivier Lantz), the Institut St Louis (Dr Michèle Goodhardt) and Génosplice (Dr Pierre de barn)
