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

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

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 1

ILY injection triggers a specific and rapid hCD59+ BEC injury leading to liver blood microcirculation impairment and inflammation in ihCD59BEC-TG mice.

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ILY injection triggers a specific and rapid hCD59+ BEC injury leading to...
ihCD59 (control group) and ihCD59BEC-TG (injured) mice were injected intravenously with ILY (140 μg/kg). Mice were euthanized, and samples were collected at the indicated time points after injection. (A) H&E and TUNEL staining was performed. Black arrows indicate injured bile ducts. Scale bars: 50 μm. (B) ALT and ALP serum levels were measured (n = 3–4 per group). (C) TBIL serum levels and liver bile acid concentrations were measured (n = 3–6 per group). (D) Relative expression of cholestasis-associated genes from snap-frozen liver homogenates (statistical analyses are shown in Supplemental Figure 1A). (E) Liver blood microcirculation from circled areas labeled 1 and 2 and portal vein pressure were measured 6 hours after ILY injection (n = 7–14 per group). Scale bar: 5 mm. (F) Relative expression of inflammation-associated genes from liver homogenates (n = 3–7 per group). Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.005, compared with control ihCD59 mice, by 1-way ANOVA (B, C, and F) and unpaired Student’s t test (E). ND, nondetectable.