Human poliovirus receptor contributes to biliary atresia pathogenesis by exacerbating natural‐killer‐cell‐mediated bile duct injury

Abstract

Background and Aims Natural killer (NK) cells play an important role in biliary atresia (BA) pathogenesis; human poliovirus receptor (PVR) is an important NK‐cell modulator. Here, we explored the role of PVR in BA pathogenesis. Methods Poliovirus receptor expression and NK cell‐associated genes were detected in human BA samples and a rotavirus‐induced BA mouse model using quantitative PCR and immunofluorescence staining. Chemically modified small interfering RNA silenced PVR expression in the BA model, and its effects on the population and function of intrahepatic NK cells were investigated using flow cytometry (FCM). The effects of PVR overexpression and knockdown on proliferation, apoptosis and NK‐cell‐mediated lysis of cultured human cholangiocytes were analysed using FCM and cell viability assays. Serum PVR, high‐mobility group box 1 (HMGB1), and interleukin‐1beta (IL‐1beta) levels were measured in a cohort of 50 patients using ELISA. Results Poliovirus receptor expression was upregulated in the biliary epithelium of BA patients and BA model and was positively correlated with the population and activation of intrahepatic NK cells. Silencing of PVR expression impaired the cytotoxicity of NK cells, reduced inflammation and protected mice from rotavirus‐induced BA. Activation of the TLR3‐IRF3 signalling pathway induced PVR expression in cultured cholangiocytes. PVR overexpression promoted proliferation and inhibited the apoptosis of cholangiocytes but exacerbated NK cell‐mediated cholangiocyte lysis. Serum PVR levels were elevated in BA patients and were positively correlated with HMGB1 and IL‐1beta levels. Conclusions Poliovirus receptor contributes to BA pathogenesis by regulating NK cell‐mediated bile duct injury; PVR has the value as a biomarker of BA.

Progress in Biomarkers Related to Biliary Atresia

“…Furthermore, PVR may be involved in the pathogenesis of BA by regulating the NK cell-mediated bile duct injury. 99 Besides, the concentration of PVR in the sera of children with BA was significantly higher than that in the sera of healthy controls. This suggests that PVR may be a potential biomarker of BA.…”

“…Biomarkers that can be used to diagnose BA have always been the focus of attention. Li et al 99 found that human poliovirus receptor (PVR) expression was upregulated in the bile ducts of patients with BA and RRV-induced BA mice. Furthermore, PVR may be involved in the pathogenesis of BA by regulating the NK cell-mediated bile duct injury.…”

“…An increasing number of serum biomarkers with diagnostic and prognostic value in BA have been discovered and promoted in recent years. Most of them are listed in Table 3, 16,[31][32][33][34][35][36][37]40,42,52,54,59,69,70,72,[75][76][77]83,87,[92][93][94][95][96][97][98][99][100][102][103][104][105][106][107][108][110][111][112][113] including all the biomarkers mentioned in this review. Among them, MMP-7 is currently the most reliable biomarker for the diagnosis of BA, which may help clinicians assess the stage of liver fibrosis and predict post-KPE outcomes to a certain extent.…”