Journal Article

Bile acid–activated macrophages promote biliary epithelial cell proliferation through integrin αvβ6 upregulation following liver injury

Qin, Xuebin, Liu, Fengming, Tacke, Frank, Gao, Bin, Feng, Dechun, He, Yong, Guillot, Adrien, Goldman, David, Ahmed, Yeni Ait, Guerri, Lucia, Pacher, Pal, Dai, Shen, Paloczi, Janos, Kim, Seung-Jin, Schuebel, Kornel, Kisseleva, Tatiana

2021

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Acids / Animals / Antigens, Neoplasm - biosynthesis / Antigens, Neoplasm - genetics / Bile / Bile Acids and Salts - genetics / Bile Acids and Salts - metabolism / Bile ducts / Biliary Tract - metabolism / Biomedical research / CCR2 protein / CD59 antigen / Cell growth / Cell Proliferation / Cholestasis / Coronaviruses / COVID-19 / Epithelial cells / Epithelial Cells - metabolism / Female / Gallbladder diseases / Gene deletion / Genes / Humans / Hypertension / Inflammation / Integrins - biosynthesis / Integrins - genetics / Liver diseases / Liver failure / Macrophage Activation / Macrophages / Macrophages - metabolism / Male / Mice / Mice, Transgenic / Monocyte chemoattractant protein 1 / Monocytes / Recruitment / RNA-Seq / Therapeutic targets / Transgenic animals / Transgenic mice / Up-Regulation