Background & aims: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease manifested with the aberrant activation of hepatic dendritic cells (HDCs) and the subsequent breakdown of immune homeostasis. As an important player, HDC maintains immunological balance between tolerance to self-antigens versus destruction against pathogens in liver. However, the intracellular signalling networks that program HDC remain unclear. We have now found the role of canonical Wnt/β-catenin signalling in HDCs.
Methods: Liver sections from AIH patients and healthy subjects were stained for the markers of Wnt/β-catenin signalling. Concanavalin A (ConA) and HDC/Hepa1-6 vaccine-induced AIH mouse models were examined for liver injury, inflammation and immune cell functions by serum biochemistry, histology, quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry analysis. Wnt/β-catenin signalling expression was measured using immunoblot and qRT-PCR.
Results: Canonical Wnt/β-catenin signalling in HDC is deficient in AIH patients and a mouse model, which coincides with the immunogenic function of HDCs. Furthermore, Wnt ligand engagement reactivates Wnt/β-catenin signalling and recovers the immunoregulatory phenotype of HDCs, in turn alleviating the severity of AIH. Likewise, pharmacologic activation of Wnt/β-catenin signalling attenuates AIH progression.
Conclusions: We report here that the constitutively active canonical Wnt/β-catenin signalling confers HDCs tolerogenicity under steady-state conditions. Deficiency of this pathway gives rise to T cell-mediated immune response and incidence of AIH. It may act as a new pathogenesis and treatment target for AIH.
Keywords: AIH; HDCs; canonical Wnt/β-catenin signalling; immune tolerance.
© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.