Inflammation Research Center (Inserm/Université Paris Cité)
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Cirrhosis is the final 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. © Adobe Stock
Chronic liver diseases are characterized by persistent inflammation that contributes to their progression to more severe stages. They may progress to fibrosis and cirrhosis, and then require liver transplantation. Therefore, limiting the progression of fibrosis and bringing about its regression is a major therapeutic challenge. Several studies have recently suggested that one interesting approach could be to target the inflammatory response. In new research, scientists from Inserm and Université Paris-Cité at the Inflammation Research Center (CRI), in collaboration with teams from the Paris Public Hospitals Group (AP-HP), have shown that blocking the activation of a particular population of T cells, the Mucosal-Associated Invariant T (MAIT) cells, could halt the progression of fibrosis and even bring about its regression. Targeting the MAIT cells involved in the inflammation seen in fibrosis and cirrhosis would therefore open up new avenues for better therapeutic care. This study has been published in Nature Communications.
Mainly alcoholic, viral, or metabolic in origin, cirrhosis is the last stage of fibrosis associated with chronic liver diseases. Cirrhosis affects between 200 000 and 500 000 people in France and is responsible for 170 000 deaths per year in Europe. Ultimately, it leads to liver failure for which the only cure is transplantation.
One characteristic of chronic liver diseases is persistent inflammation that contributes to their progression to more severe stages, particularly fibrosis and its final stage, cirrhosis. A better understanding of how to regulate this inflammatory response therefore constitutes a major challenge in developing new strategies to treat these diseases.
In 2018, the team of Inserm researcher Sophie Lotersztajn had shown that a population of T cells called MAIT promoted 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 on the basis of liver samples from cirrhotic patients as well as from mouse models of the disease.
They showed that the administration of a pharmacological agent to inhibit the activation of MAIT cells can limit liver inflammation and not only halt the progression of fibrosis, but also regress it.
It is now well known that other immune cells, such as the macrophages, play a central role in the progression and regression of fibrosis. Here, analysis of the mechanisms involved showed that blocking the activation of MAIT cells interrupts their dialog with profibrogenic macrophages, i.e. accelerators of fibrosis, and promotes the emergence of fibrosis-resolutive macrophages.
In the first image, the MAIT cells (in red, shown using arrows) are located near fibrogenic cells (in green) in the liver of cirrhotic patients. In the second image, the MAIT cells (in red) are activated (activation marker in green) in the liver of cirrhotic patients. This activation is blocked in the presence of a MAIT cell inhibitor. Credits: Sophie Lotersztajn
“Cirrhosis is a major public health problem. Even though the only treatment is liver transplantation, our research opens up other therapeutic avenues for targeting inflammation and halting or even regressing fibrosis. The research now needs to be continued, particularly in order to develop drug candidates that target and inhibit the MAIT cells,” concludes Lotersztajn.
 This research is the result of a collaboration between the team of Drs. Sophie Lotersztajn and Hélène Gilgenkrantz (Inflammation Research Center (CRI) Inserm-Université Paris Cité), the team of Dr. Valérie Paradis at the CRI (also Department of Pathology, Beaujon Hospital), Department of Anesthesiology and Critical Care (Prof. Emmanuel Weiss), the teams of Institut Curie (Dr. Olivier Lantz), Institut St Louis (Dr. Michèle Goodhardt) and Génosplice (Dr. Pierre de la Grange)
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MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming
Morgane Mabire1, Pushpa Hegde1, Adel Hammoutene1,7, Jinghong Wan1,7, Charles Caër1,7, Rola Al Sayegh1, Mathilde Cadoux1, Manon Allaire1, Emmanuel Weiss1,2, Tristan Thibault-Sogorb1,2, Olivier Lantz3, Michèle Goodhardt4, Valérie Paradis1,5, Pierre de la Grange6, Hélène Gilgenkrantz1 & Sophie Lotersztajn1
1 Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex, F-75018 Paris, France.
2 Département d’Anesthésie et Réanimation, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, 92110 Clichy, France.
3 Institut Curie, INSERM U932, Paris, France.
4 Université Paris Cité, INSERM UMRS 976, Institut de Recherche Saint Louis, F-75010 Paris, France.
5 Département de Pathologie, HôpitalBeaujon, Assistance Publique-Hôpitaux de Paris, 92110 Clichy, France.
6 GenoSplice, Paris, France.
7 These authors contributed equally
Nature Communication, avril 2023