title: The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia.
abstract: Biliary atresia (BA) 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. Interleukin 17A (IL-17A)-green fluorescent protein, cluster of differentiation 11c (CD11c)/diphtheria toxin receptor, and IL-17 receptor A-/-mice were used to examine T-lymphocyte polarization, inflammatory leukocyte recruitment, and biliary injury in rhesus rotavirus-induced BA. Multiparameter flow cytometry and automated image analysis of immunostaining were applied to liver tissue samples from infants with BA. 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 concomitantly with hepatic accumulation of T helper 17 lymphocytes and myeloid dendritic cells. Targeted depletion of CD11c+dendritic cells diminished hepatic IL-17A production and ameliorated intrahepatic bile duct injury. Recombinant IL-17A induced expression of chemokine (C-C motif) ligand 2 in neonatal cholangiocytes in vitro, and blockade of the corresponding chemokine (C-C motif) receptor 2 reduced recruitment of inflammatory macrophages to the liver in vivo. Genetic disruption of IL-17A signaling was associated with down-regulation of hepatic Ccl2/Ccr2 messenger RNA expression, reduced infiltration of the liver with inflammatory Ly6Chimacrophages, and improved survival. In the liver of infants with BA, 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 undergoing liver transplantation.
  
  
  
  These findings identify the dendritic cell-T helper 17-macrophage axis as a target for the development of strategies to block progression of intrahepatic bile duct injury in patients with BA. (Hepatology 2017;65:174-188).
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Celine S
authors.initials: CS
authors.lastname: Lages
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Julia
authors.initials: J
authors.lastname: Simmons
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Avery
authors.initials: A
authors.lastname: Maddox
authors.affiliation: University of Cincinnati, College of Medicine, Internal Medicine Residency Program, Cincinnati, OH.
authors.forename: Keaton
authors.initials: K
authors.lastname: Jones
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Karns
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Rachel
authors.identifier: 0000-0002-8318-8920
authors.initials: R
authors.lastname: Sheridan
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Shiva Kumar
authors.initials: SK
authors.lastname: Shanmukhappa
authors.affiliation: Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Sujit
authors.initials: S
authors.lastname: Mohanty
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Matthew
authors.initials: M
authors.lastname: Kofron
authors.affiliation: Division of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Russo
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Yui-Hsi
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Claire
authors.initials: C
authors.lastname: Chougnet
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Miethke
mesh_terms: D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000166:cytology; D001656:Biliary Atresia / Q000276:immunology*; D003713:Dendritic Cells / Q000502:physiology*; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D058504:Th17 Cells / Q000502:physiology*