Zhejiang University: Therapeutic potential of zVAD in autoimmune hepatitis

Autoimmune hepatitis (AIH) is an immune-mediated inflammatory disease. The incidence andprevalence of AIH are increasing. In addition, AIH is associated with an increased risk of death from cardiovascular disease, liver disease and extrahepatic malignancy. However, there are no specific therapies for AIH. Currently, the only viable treatments for AIH are immunosuppressant therapy and liver transplantation; however, these standard therapies are associated with side effects and non-responsiveness. Thus, there is a need to investigate the pathogenesis of AIH and to find a practical and effective treatment for this condition.

Immunotherapies have the potential to advance the treatment of autoimmune liver diseases, which are largely driven by immune cells, including macrophages. Uncontrolled, classically activated macrophages (M1) can promote immunopathology by producting pro-inflammatory cytokines. Thus, decreasing the levels of pro-inflammatory cytokines by decreasing the number of macrophages is an effective approach to control the aggravation of acute liver injury. Recently, the research team led by Prof. DIAO Hongyan from the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZU) found that zVAD alleviated ConA-induced liver injury by increasing the sensitivity of macrophages to necroptosis via IL-10-induced TNFR1 expression. This study provides new insights into the treatment of autoimmune hepatitis via zVAD-induced macrophage necroptosis. Their research findings were published in Journal of Autoimmunity (IF=14.511), entitled “zVAD alleviates experimental autoimmune hepatitis in mice by increasing the sensitivity of macrophage to TNFR1-dependent necroptosis”.

In this study, DIAO’s group first found that zVAD increased necroptosis in experimental AIH in mice, and that zVAD not only induced necroptosis but also markedly alleviated liver injury. The percentage of macrophages and neutrophils decreased after zVAD pretreatment, but not in the same manner as NK, NKT, and conventional T cells. Additionally, zVAD markedly decreased the levels of pro-inflammatory cytokines in the liver and serum. The mechanism studies show thatzVAD decreases the levels of pro-inflammatory cytokines and chemokine by increasing macrophage necroptosis.In addition, zVAD increases the sensitivity of macrophages to necroptosis via IL-10-induced TNFR1 increment.

This study demonstrated that zVAD alleviated ConA induced liver injury by increasing macrophage necroptosis, which verified the key role of macrophage in this disease. In addition, this work showed that zVAD increases the sensitivity of macrophages to necroptosis via IL-10-induced TNFR1 increment. These findings extend the previous understanding of zVAD-induced necroptosis and provides new insights into the treatment of AIH.