Dendritic Cells Regulate Treg-Th17 Axis in Obstructive Phase of Bile Duct Injury in Murine Biliary Atresia

Yong-Jun Liu,Kang Li,Xin-Xing Wang,Li Yang,Guo-Qing Cao,Xi Zhang,Shao-Tao Tang,Hai-Yan Lei,Shuai Li,Gianfranco Alpini

doi:10.1371/journal.pone.0136214

Yong-Jun Liu, Kang Li + Show 8 more

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https://doi.org/10.1371/journal.pone.0136214

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Abstract

Several cell types are considered to be effector cells in bile duct injury in rhesus rotavirus (RRV)-induced experimental biliary atresia (BA). Here, we identified an increased T helper 17 (Th17) cell population in a BA mode. By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved. Furthermore, we found that in mice with BA, the percentage of CD4+CD25highFoxp3+ T regulatory (Treg) cells decreased along with the increased percentage of Th17 cells. However, the absolute numbers of Treg and Th17 cells were both increased in liver of RRV-injected mice compared to saline-injected mice. The proportion of Th17 cells at 7 days post-infection was decreased if Treg cells isolated from normal adult mice, but not Treg cells from the livers of mice with BA, were intraperitoneally transferred on day 5 of life. In vitro experiments also showed that Treg cells from mice with BA had a diminished suppressive effect on Th17 cell generation. To determine the mechanisms, we investigated the production of cytokines in the liver. The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated. Importantly, in a Treg/Th17 cell suppression assay, IL-6 was demonstrated to paralyze the Treg cells’ suppressive effect on Th17 cells and eventually the unrestrained increase of Th17 cells contributed to bile duct injury. In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.

Highlights

Biliary atresia (BA) consists of embryonic and perinatal types, based on its clinical pathogenesis
To determine whether T helper 17 (Th17) cells have a role in biliary destruction during BA pathogenesis, we first showed that CD4+IL-17A+ T cells infiltrated into portal areas by immunofluorescence staining (Fig 1A)
We previously demonstrated that Th17 cell numbers were increased and IL-17A levels were elevated in the liver of infants with BA [13]

Summary

Introduction

Biliary atresia (BA) consists of embryonic (fetal or prenatal; 20%) and perinatal (acquired; 80%) types, based on its clinical pathogenesis. The perinatal type is characterized by progressive inflammation, sclerosing cholangiopathy and obstruction of both the extrahepatic and the intrahepatic bile ducts. Treg-Th17 Axis in Murine Biliary Atresia studies have suggested that BA is an immune-mediated disease [1,2] and studies utilizing a rotavirus-induced BA mouse model have established further evidence for a virus-induced autoimmune pathway [3,4]. Experimental and clinical studies have proven that CD4+ T cells are implicated in the pathogenesis of BA, resulting in an augmentation of CD4+ T helper 1 (Th1) cells [5] and a depletion of T regulatory (Treg) cells [6]. The precise mechanisms by which the immune system is modulated in patients with BA remains unknown

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