The dendritic cell–T helper 17–macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia

Lages, Celine S.; Simmons, Julia; Maddox, Avery; Jones, Keaton; Karns, Rebekah; Sheridan, Rachel; Shanmukhappa, Shiva Kumar; Mohanty, Sujit K.; Kofron, Matthew; Russo, Pierre; Wang, Yui‐Hsi; Chougnet, Claire; Miethke, Alexander

doi:10.1002/hep.28851

Cited by 44 publications

(38 citation statements)

References 28 publications

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“…Despite a prominent type 1 inflammatory response, studies in humans and mice also show a Th17 commitment and its correlation with disease progression . In addition, livers and sera from a subgroup of BA patients have high levels of type 2 cytokines, such as IL‐13, IL‐33, and IL‐4 .…”

Section: Basic Researchmentioning

confidence: 99%

Biliary Atresia: Clinical and Research Challenges for the Twenty‐First Century

et al. 2018

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Biliary atresia (BA) is a fibroinflammatory disease of the intra- and extrahepatic biliary tree. Without medical treatment, surgical hepatic portoenterosmy (HPE) may restore bile drainage, but progression of the intrahepatic disease results in complications of portal hypertension and advanced cirrhosis in most children. Recognizing that further progress in the field is unlikely without a better understanding of the underlying cause(s) and pathogenesis of the disease, the National Institutes of Diabetes and Digestive and Kidney Diseases sponsored a research workshop focused on innovative and promising approaches and on identifying future areas of research. Investigators discussed recent advances using gestational ultrasound and results of newborn BA screening with serum direct (conjugated) bilirubin that support a pre-natal onset of biliary injury. Experimental and human studies implicate the toxic properties of environmental toxins (e.g. biliatresone) and of viruses (e.g. CMV) to the biliary system. Among host factors, sequence variants in genes related to biliary development and ciliopathies, a notable lack of a cholangiocyte glycocalyx and of submucosal collagen bundles in the neonatal extrahepatic bile ducts, and an innate pro-inflammatory bias of the neonatal immune system contribute to an increased susceptibility to damage and obstruction following an epithelial injury. These advances form the foundation for a future research agenda focused on identifying the environmental and host factor(s) that cause BA, the potential use of population screening, studies of the mechanisms of prominent fibrosis in young infants, determinations of clinical surrogates of disease progression, and the design of clinical trials that target subgroups of patients with initial drainage following HPE. This article is protected by copyright. All rights reserved.

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Section: Basic Researchmentioning

confidence: 99%

Biliary Atresia: Clinical and Research Challenges for the Twenty‐First Century

et al. 2018

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“…Among all viruses, rhesus rotavirus type A (RRV) is the gold standard to model BA in mice. The use of this murine model has facilitated the study of different aspects of the disease, such as the underlying mechanisms of the pathogenesis (26)(27)(28)(46)(47)(48)(49)(50) or the identification of novel therapeutic targets (51). This experimental form of BA uses BALB/c newborn mice that, when challenged with RRV within the first hours of life (12-48 h), can recapitulate many aspects of human BA (52) such as time-restricted susceptibility to the viral infection, portal tract infiltration of inflammatory cells and obstruction of both extrahepatic and intrahepatic biliary tree (5,34).…”

Section: Rhesus Rotavirus-induced Murine Modelmentioning

confidence: 99%

“…In this study, a model of biliary injury perpetuation was proposed in which IL-17A stimulated cholangiocytes to produce C-C motif chemokine ligand 2 (CCL2) that recruited inflammatory macrophages expressing IL-17AR to target the epithelium (51), as shown in Figure 4B. In this model, depletion of Th17 cells or blockage of CCL2 prevented bile duct paucity and the number of Th17 cells correlated with the concentration of gamma glutamyl transpeptidase (GGT), a biochemical marker of bile duct injury (51). In BA patients, the presence of Th17 in the biliary tree and peripheral blood has been confirmed, as well as Th17-related markers in liver tissue [IL-17A and retinoic acid-related orphan receptor (ROR)-γt] and serum IL-23.…”

Section: Mechanisms Of Post-obstruction: Chronic Inflammation Duct Pmentioning

confidence: 99%

Innate Immunity and Pathogenesis of Biliary Atresia

et al. 2020

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Biliary atresia (BA) is a devastating fibro-inflammatory disease characterized by the obstruction of extrahepatic and intrahepatic bile ducts in infants that can have fatal consequences, when not treated in a timely manner. It is the most common indication of pediatric liver transplantation worldwide and the development of new therapies, to alleviate the need of surgical intervention, has been hindered due to its complexity and lack of understanding of the disease pathogenesis. For that reason, significant efforts have been made toward the development of experimental models and strategies to understand the etiology and disease mechanisms and to identify novel therapeutic targets. The only characterized model of BA, using a Rhesus Rotavirus Type A infection of newborn BALB/c mice, has enabled the identification of key cellular and molecular targets involved in epithelial injury and duct obstruction. However, the establishment of an unleashed chronic inflammation followed by a progressive pathological wound healing process remains poorly understood. Like T cells, macrophages can adopt different functional programs [pro-inflammatory (M1) and resolutive (M2) macrophages] and influence the surrounding cytokine environment and the cell response to injury. In this review, we provide an overview of the immunopathogenesis of BA, discuss the implication of innate immunity in the disease pathogenesis and highlight their suitability as therapeutic targets.

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“…Furthermore, liver tissue from BA patients at diagnosis had significantly increased levels of IL-17 mRNA [77]. Lages et al showed that CD4+ T cells were primarily responsible for IL-17 production and IL-17 stimulated macrophage influx and biliary injury in the mouse model [78]. Analysis of human tissue reveals that high expression of IL-17 producing T cells was associated with need for liver transplant.…”

Section: T-cell Immunitymentioning

confidence: 99%

Update on investigations pertaining to the pathogenesis of biliary atresia

Kilgore

Mack

2017

Pediatr Surg Int

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Biliary atresia is a devastating biliary disease of neonates that results in liver transplantation for the vast majority. The etiology of biliary atresia is unknown and is likely multifactorial, with components of genetic predisposition, environmental trigger and autoimmunity contributing to disease pathogenesis. This review highlights recent work related to investigations of disease pathogenesis in biliary atresia.

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The dendritic cell–T helper 17–macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia

Cited by 44 publications

References 28 publications

Biliary Atresia: Clinical and Research Challenges for the Twenty‐First Century

Biliary Atresia: Clinical and Research Challenges for the Twenty‐First Century

Innate Immunity and Pathogenesis of Biliary Atresia

Update on investigations pertaining to the pathogenesis of biliary atresia

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