https://www.ncbi.nlm.nih.gov/pubmed/27641439

Lages CS, Simmons J, Maddox A, Jones K, Karns R, Sheridan R, Shanmukhappa SK, Mohanty S, Kofron M, Russo P, Wang YH, Chougnet C, Miethke AG.

Hepatology. 2016 Sep 19. doi: 10.1002/hep.28851.

Abstract

Biliary atresia is a fibroinflammatory obstruction of the extrahepatic biliary tree in neonates. While intrahepatic bile duct proliferation is universal at diagnosis, bile duct paucity develops later. We hypothesized that polarized T helper lymphocyte responses orchestrate progression of intrahepatic biliary injury in this disease. IL-17A-GFP, CD11c/DTR and IL17RA-/- mice were used to examine T-lymphocyte polarization, inflammatory leukocyte recruitment and biliary injury in rhesus-rotavirus induced biliary atresia. Multiparameter flow cytometry and automated image analysis of immunostaining were applied to liver tissue samples from infants with biliary atresia. In the mouse model, activated CD4+ lymphocytes started to emerge in the liver on day 8 after viral challenge while innate immune responses were waning. Plasma IL-17A levels rose concomitant with hepatic accumulation of Th17 lymphocytes and myeloid dendritic cells. Targeted depletion of CD11c+ dendritic cells diminished hepatic IL-17A production and ameliorated intrahepatic bile duct injury. Recombinant IL17A induced expression of CCL2 in neonatal cholangiocytes in vitro, and blockade of the corresponding chemokine receptor CCR2 reduced recruitment of inflammatory macrophages to the liver in vivo. Genetic disruption of IL-17A signaling was associated with downregulation of hepatic Ccl2/Ccr2 mRNA expression, reduced infiltration of the liver with inflammatory Ly6Chi macrophages and improved survival. In the liver of infants with biliary atresia, cholangiocytes were found to express IL-17 receptor A and the prevalence of IL-17A+ cells was positively correlated with the degree of CD68+ macrophage infiltration at diagnosis. Hepatic CD4+ lymphocytes were chief producers of IL-17A in patients with progressive disease undergoingliver transplantation.

CONCLUSION:
Our findings identify the dendritic cell-Th17-macrophage axis as target for the development of strategies to block progression of intrahepatic bile duct injury in patients with biliary atresia.