Liver fibrosis is defined by the excessive accumulation of connective tissue proteins in the liver, which replace healthy tissue and disrupt the liver’s appearance and function. The progression of fibrosis may eventually necessitate a liver transplant or lead to cirrhosis, a leading cause of death in the United States. Fortunately, fibrosis can be reversed if diagnosed early, highlighting the need for therapeutic interventions to interrupt and reverse fibrosis before the late stages of the disease.
IL-17 Initiates Fibrosis
Several inflammatory cytokines are involved in the fibrogenic process, including IL-17A, which participates in the initiation and progression of liver fibrosis. The retinoic acid receptor-related orphan receptor gamma t (RORγt) is involved in the differentiation of IL-17A-producing cells, such as γδ-T cells, which are increasingly recognized as a major source of IL-17A. RORγt is therefore a highly attractive therapeutic target in IL-17-mediated diseases, like liver fibrosis.
A new study published in The Journal of Immunology, led by Dr. Naglaa Shoukry, Director of the Laboratory of Liver Immunology at the University of Montreal, utilized a mouse model to evaluate the efficacy of RORγt inhibitors in treating liver fibrosis. The researchers found that treating mice with the RORγt inhibitors TF-S10 and TF-S14, developed by Dr. Jean Tchervenkov, a Professor at McGill University, improved the appearance and function of the liver.
To induce liver injury, mice were given weekly injections of CCl4 for four weeks, which induced inflammation and fibrosis in the liver similar to that seen in the livers of individuals with drug toxicity. After two weeks, mice were treated daily with a combination of TF-S10 and TF-S14 or GSK805, a positive control.
Reversal of Fibrosis
Livers of treated mice showed reduced inflammation, as indicated by a lower number of infiltrating immune cells, specifically Th17 cells. Additionally, treating the mice with RORγt inhibitors resulted in reduced liver fibrosis. Treated livers also exhibited less activation of hepatic stellate cells—cells typically involved in producing collagen—thereby demonstrating lower deposition of collagen.
“We saw that the short-term impact of RORγt inhibitors can be both anti-inflammatory and antifibrotic. We hope in the long run, RORγt inhibitors will reduce chronic inflammation, reverse established fibrosis, and slow or prevent progression to cirrhosis thereby improving patients’ lives,” said Dr. Afrooz Dabbaghizadeh, lead author on the study.
“Our study suggests inhibition of the IL-17 pathway may be a promising therapeutic strategy for patients with liver fibrosis and thus paves the way for the development of novel therapeutic agents and strategies,” shared Dr. Shoukry.
As the CCl4-induced liver injury in mice is a short-term injury, next steps for the research team are to assess the therapeutic potential of the RORγt inhibitors in a mouse model of chronic liver fibrosis.
This paper can be found in The Journal of Immunology (The JI), published by the American Association of Immunologists. As one of the most highly cited journals in the field of immunology, The JI is committed to describing novel findings in all areas of experimental immunology, including basic and clinical studies.
Image featuring a liver sample with trichrome stain showing cirrhosis surrounded by fibrosis courtesy of Ed Uthman, Pathologist, Houston, TX, USA
