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Bile acid–activated macrophages promote biliary epithelial cell proliferation through integrin αvβ6 upregulation following liver injury
Adrien Guillot, … , Frank Tacke, Bin Gao
Adrien Guillot, … , Frank Tacke, Bin Gao
Published March 16, 2021
Citation Information: J Clin Invest. 2021;131(9):e132305. https://doi.org/10.1172/JCI132305.
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Research Article Hepatology Article has an altmetric score of 16

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

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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.

Authors

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

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Figure 3

xMD and RNA-Seq identify ITGβ6 as one of the most upregulated genes in BECs after acute, targeted BEC death.

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xMD and RNA-Seq identify ITGβ6 as one of the most upregulated genes in B...
ihCD59 and ihCD59BEC-TG mice were injected intravenously with ILY. (A) Fresh-frozen liver tissue sections collected 48 hours after ILY injection were stained with a CK19 antibody using an RNA-friendly staining protocol, followed by purification of CK19+ biliary cells by xMD and transcriptome RNA-Seq analysis (n = 2 in each group, as detailed in Supplemental Figure 3). Representative CK19 immunostaining on frozen liver sections and leftover versus lifted-off samples are shown. Only purified BECs (lifted off) were used for RNA-Seq and analysis. Scale bar: 100 μm. (B) GO term enrichment analysis of differentially expressed genes between the control and injured groups. GO terms comprising integrin αvβ6 (Itgb6) are shown with a red star. (C) Heatmap of differentially expressed genes between the injured and control groups. (D) Volcano plot of expressed genes (RPKM ≥0.05). Differentially expressed genes (FDR ≤0.05) between the injured and control groups are shown in red.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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