Preferential TNFα signaling via TNFR2 regulates epithelial injury and duct obstruction in experimental biliary atresia

Biliary atresia is an obstructive cholangiopathy of infancy that progresses to end-stage cirrhosis. Although the pathogenesis of the disease is not completely understood, previous reports link TNF alpha to apoptosis of the bile duct epithelium in the presence of IFN gamma. Here, we investigate if TNFa signaling regulates pathogenic mechanisms of biliary atresia. First, we quantified the expression of TNFA and its receptors TNFR1 and TNFR2 in human livers and found an increased expression of the receptors at the time of diagnosis. In mechanistic experiments using a neonatal mouse model of rhesus rotavirus-induced (RRV-induced) biliary atresia, the expression of the ligand and both receptors increased 6-to 8-fold in hepatic DCs and NK lymphocytes above controls. The activation of tissue NK cells by RRV-primed DCs was independent of TNF alpha-TNFR signaling. Once activated, the expression of TNF alpha by NK cells induced lysis of 55% +/- 2% of bile duct epithelial cells, which was completely prevented by blocking TNFa or TNFR2, but not TNFR1. More notably, antibody-mediated or genetic disruption of TNF alpha(TNFR2 signaling in vivo decreased apoptosis and epithelial injury; suppressed the infiltration of livers by T cells, DCs, and NK cells; prevented extrahepatic bile duct obstruction; and promoted long-term survival. These findings point to a key role for the TNF alpha/TNFR2 axis on pathogenesis of experimental biliary atresia and identify new therapeutic targets to suppress the disease phenotype.