Abstract
Cholangiopathies caused by biliary epithelial cell (BEC) injury represent a leading cause of liver failure. No effective pharmacologic therapies exist, and the underlying mechanisms remain obscure. We aimed to explore the mechanisms of bile duct repair after targeted BEC injury. Injection of intermedilysin into BEC-specific human CD59 (hCD59) transgenic mice induced acute and specific BEC death, representing a model to study the early signals that drive bile duct repair. Acute BEC injury induced cholestasis followed by CCR2+ monocyte recruitment and BEC proliferation. Using microdissection and next-generation RNA-Seq, we identified 5 genes, including Mapk8ip2, Cdkn1a, Itgb6, Rgs4, and Ccl2, that were most upregulated in proliferating BECs after acute injury. Immunohistochemical analyses confirmed robust upregulation of integrin αvβ6 (ITGβ6) expression in this BEC injury model, after bile duct ligation, and in patients with chronic cholangiopathies. Deletion of the Itgb6 gene attenuated BEC proliferation after acute bile duct injury. Macrophage depletion or Ccr2 deficiency impaired ITGβ6 expression and BEC proliferation. In vitro experiments revealed that bile acid-activated monocytes promoted BEC proliferation through ITGβ6. Our data suggest that BEC injury induces cholestasis, monocyte recruitment, and induction of ITGβ6, which work together to promote BEC proliferation and therefore represent potential therapeutic targets for cholangiopathies.
Highlights
The biliary tree occupies a substantial space in the liver and has crucial functions such as the transport and maturation of bile [1]
In order to decipher the immunological mechanisms implicated in bile duct injury and repair, and because most mouse liver injury models are associated with strong injury to both hepatocytes and biliary epithelial cell (BEC), we took advantage of our recently developed model of targeted acute BEC injury in ILY-treated, BEC-specific mice [16] and characterized bile duct repair after acute injury
Cholestasis was evidenced by an increase in bile acid concentrations in liver homogenates (Figure 1C), and a dysregulation of bile acid metabolism–related gene (Fxr, G protein-coupled bile acid receptor 1 (Gpbar1), Cyp7a1, Cyp8b1) expression
Summary
The biliary tree occupies a substantial space in the liver and has crucial functions such as the transport and maturation of bile [1]. Classical clinical presentations for these disorders include cholestasis and portal inflammation, fibrosis, as well as portal hypertension and disturbances of the liver microcirculation [4]. Ductular reaction, which involves biliary epithelial or liver progenitor cell proliferation as well as portal inflammation and portal fibrosis, is observed in numerous hepatopathies and is notably associated with a poor outcome in chronic liver diseases of various etiologies [5, 6]. Several studies reported a potent role for immune cells in promoting the ductular reaction [5, 7,8,9], the precise mechanisms underlying bile duct injury and regeneration have not been identified because of the lack of a specific biliary epithelial cell (BEC) injury model
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