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Montreal, October 26, 2018 – Naglaa Shoukry, Ph.D., and her team have made significant progress in their research to limit the progression of liver disease. They have characterized the mechanisms of action of inflammatory cytokines type 3 produced by the cells of the immune system, resulting in a progression of liver scarring called fibrosis. These research efforts have identified new potential targets for inhibiting the progression of liver disease and preventing cancer.
Researchers at the Liver Immunology Research Unit of the Research Center of the University Hospital of Montreal (CRCHUM) have discovered how a protein called interleukin 22 (IL-22) accelerates fibrosis Episodes of chronic hepatitis by amplifying the signal of the fibrogenic cytokine TGF-β. The fibrogenic nature of IL-22 was unknown until now. This new discovery allows us to understand its interaction when it is badociated with TGF-β, a cytokine produced during inflammation of the liver. Indeed, cases of advanced fibrosis confirm the pathogenic appearance of IL-22.
Another type 3 cytokine, namely interleukin 17A (IL-17A), was known to be an agent enhancing inflammation and fibrosis leading to cirrhosis of the liver, possibly causing cancer. The team identified neutrophils and mast cells as the major source of IL-17A in humans. Indeed, their number increases in the immune system-induced inflammation during liver disease.
It now appears that two type-3 cytokines, IL-17A and IL-22, can, by independent mechanisms, sensitize hepatic stellate cells (HSCs) to the action of TGF-β. HSCs, thus more sensitized to proliferation and fibrosis signals, remodel the extracellular matrix, leading to a deterioration in the architecture and function of the affected patient's liver.
Successful experiments to block the production of IL-17A and IL-22
The balance between the two cytokines IL-17A and IL-22 during the different stages of liver disease and their combined roles remain unknown and further studies are needed. However, experiments on mice have shown that the inhibition by small molecules of programs badociated with the production of IL-17A and IL-22 delays the development of hepatic fibrosis. These findings allow us to better characterize the pathogenic role of type 3 cytokines and to determine how to intervene to prevent the development of fibrosis and liver cancer.
The next steps
The next steps will determine when the IL-17A and IL-22 producing cells receive the signal of penetration into the liver, triggering a tissue repair reaction. The goal will be to examine how the balance between pro-inflammatory and anti-inflammatory signals is disrupted, as this is how the progression of fibrosis is influenced. Since the replacement of healthy tissue by scar tissue promotes the development of more serious pathologies, such as cirrhosis of the liver and liver cancer, it is essential to learn how to block the entry of inflammatory cells. which could over time induce cancer. . The different types of treatment, as well as the frequency and intensity of doses to block the effects of type 3 responses, need to be pursued in preclinical mouse models before finally being tested in patients. ;man. Drugs already developed for the treatment of psoriasis in humans successfully target type 3 cytokines such as IL-17 and IL-22. This avenue looks promising.
Prevalence of liver disease in Canada and Quebec
It is estimated that eight million Canadians are affected by liver disease, a disease that has little or no symptoms and can affect everyone. Chronic liver disease can lead to fibrosis, cirrhosis and liver cancer. An increase in the risk of liver disease, including non-alcoholic fatty liver disease (NASH), chronic hepatitis B and C, and liver cancer, is why, in just 10 years, the number of Canadians affected by an illness liver has increased from 1 in 10 to 1 in 4. Our nutrition, sedentary behavior and lifestyle are the main causes. This scientific breakthrough could help develop strategies to limit the development and progression of fibrosis.
Naglaa Shoukry and her team's research interests
Naglaa Shoukry, Ph.D., and her team's work focus on the immune response against the hepatitis C virus (HCV), an infection that affects approximately 71 million individuals worldwide and who is a major cause of chronic liver disease, including cancer. The team is also interested in understanding the role of immune regulation in the progression of liver fibrosis and the development of liver cancer. In particular, it examines the complementary and sometimes opposite roles of IL-17 and IL-22 in hepatic fibrosis and cancer, as well as inflammatory cell populations compared to the regulatory cells involved in this process.
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The discovery, published today in Science Immunology, was the work of a multidisciplinary research team composed of Thomas Fabre, Manuel Flores Molina (graduate students from the University of Montreal), Genevieve Soucy (Department of Pathology of the CHUM), Jean-Philippe Goulet (Caprion ), Bernard Willems, Jean-Pierre Villeneuve and Marc Bilodeau (Department of Hepatology CHUM). For more information, see the study: http: // immunology.
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