Introduction
Autoimmune hepatitis (AIH) is a chronic self-perpetuating liver inflammatory disease that affects all ages, both genders, and all ethnicities (Mack et al. , 2019). AIH may start with an episode of acute hepatitis and eventually lead to liver cirrhosis, liver cancer, the need for liver transplantation, or death (Manns et al. , 2015). The precise etiology of AIH is unknown, but it is been widely believed that natural killer T (NKT) cells and conventional T cells contribute to AIH-induced liver damage (Mattner, 2013; Mieli-Vergani et al. , 2018). The prominent features of these two cell populations during AIH include an accumulation in the liver, aberrant activation, and imbalanced Th1/Th2 responses (Senaldi et al. , 1992; Santodomingo-Garzon et al. , 2011). Once a T cell-mediated autoimmune response is initiated, hepatocytes can potentially be destroyed directly through Fas/Fas ligand (FasL) interactions and/or the action of TNF-α and perforins/granzyme B, or indirectly through the release of Th1-biased IFN-γ (Mieli-Vergani et al. , 2018). Therefore, T cells are expected to be the therapeutic targets in the treatment of AIH.
The mainstay of treatment for AIH is immunosuppression (Vergani et al. , 2012). Concanavalin A (Con A)-induced acute hepatitis in mice is considered to be a well-characterized model for studying the pathogenesis of AIH and screening immunosuppressive agents (Tiegset al. , 1992). Con A primarily stimulates the recruitment and activation of NKT and conventional T cells, coinciding with the generation of large amounts of proinflammatory Th1 cytokines (Heymann et al. , 2015). In recent years, based on the administration of Con A to model animals, many new therapeutic drugs, antibodies, and proteins have been developed to attenuate liver injury by inhibiting NKT/T cell activation and skewing (Wang et al. , 2012).
Fungus-derived natural products and their derivatives, such as cyclosporine and mycophenolate mofetil, are widely used in the treatment of autoimmune diseases (Lee et al. , 2008; Fakih et al. , 2018). Preparations of fungi and their metabolites have a low synthetic cost, high practical value, and broad application in medicine, thanks to their wide availability and high biological activity (Sharma et al. , 2016). In a previous screening of anti-inflammatory agents, we found that secoemestrin C (Fig. 1A), isolated from Aspergillus nidulans , had a potent inhibitory effect on Con A-induced splenocyte proliferation, suggesting potential immunosuppressive and anti-inflammatory activity. In the present study, we sought to investigate whether secoemestrin C could protect against Con A-induced autoimmune hepatitis in mice and to explore potential mechanisms for such an effect.