Deficiency of canonical Wnt/β‐catenin signalling in hepatic dendritic cells triggers autoimmune hepatitis

Abstract

Background & AimsAutoimmune 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.MethodsLiver 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.ResultsCanonical 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.ConclusionsWe 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.

Critical roles of conventional dendritic cells in autoimmune hepatitis via autophagy regulation

“…Therefore, an increase in this molecule might lead to the overreaction of cDCs, which results in systematic immune imbalance. Quantitative and functionality alterations of human DC cells have been reported in many autoimmune diseases [25][26][27][28][29] , yet the role of cDC in AIH has been elusive. Using the fresh peripheral blood and liver section of AIH patients and healthy controls, we demonstrated that mature cDCs played a detrimental role in promoting AIH, and then, a mouse EAH model was used to validate the phenomenon.…”

“…The autophagy process is often used to eliminate damaged or unwanted organelles and remove intracellular microbial pathogens, which play a significant role in the pathogenesis of liver disease 32,33 . Role of autophagy in dendritic cells have been reported to be associated with the following mechanisms: (i) autophagic pathways could promote MHC-II antigenpresentation, that is, autophagy could be used to direct pathogens into autophagosomes and then the fusion with lysosomes, 28,[34][35][36] (ii) autophagy could down-regulate antigen presentation on MHC-I molecules during anti-viral CD8 + T cell responses, 37,38 (iii) autophagy could accelerate cytokine production 39,40 . Most studies have found that autophagy enhancement was associated with BMDC maturation and antigen presentation after activation of Toll-like receptor (TLR) signaling pathways [41][42][43] , while other studies identified that new drug therapies could decrease DC maturation and function by enhanced autophagy 44,45 .…”

Study on Protection of Human Umbilical Vein Endothelial Cells from Amiodarone‐Induced Damage by Intermedin through Activation of Wnt/β‐Catenin Signaling Pathway

“…Application of Wnt signaling agonists increased the activity of SOD and GSH-PX and improved behavioral deficits in rats with Parkinson's disease [ 40 ]. The deficiency of this pathway gives rise to T cell-mediated immune response and incidence of AIH [ 41 ]. The Wnt/ β -catenin plays an anti-inflammatory effect on pigs during bacterial infection [ 42 ].…”

Characterization and functional prediction of the microRNAs differentially expressed in a mouse model of concanavalin A-induced autoimmune hepatitis

“…Hepatic dendritic cell (HDC), as a unique organ-resident DCs subtype, was the major contributor to sustain tolerance conditions in liver 56 .One latest study reported that the deficiency of Wnt signaling pathway in HDCs was found in both AIH patients and the Con A- induced AIH mouse model, and reinvigorating this signaling with a Wnt agonist successfully alleviated the progression of AIH. It is indicated that Wnt signaling pathway in HDCs exerts vital functions on maintenance of the liver homeostasis and their loss altered the immune environment to T cell activation 57 . The Hippo signaling pathway, which is evolutionarily conserved, has multiple biological functions in homeostasis and regeneration of tissues or organs.…”