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Bile acid-activated macrophages promote biliary epithelial cell proliferation through integrin αvß6 upregulation following liver injury.
Guillot, Adrien; Guerri, Lucia; Feng, Dechun; Kim, Seung-Jin; Ahmed, Yeni Ait; Paloczi, Janos; He, Yong; Schuebel, Kornel; Dai, Shen; Liu, Fengming; Pacher, Pal; Kisseleva, Tatiana; Qin, Xuebin; Goldman, David; Tacke, Frank; Gao, Bin.
Afiliación
  • Guillot A; Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA.
  • Guerri L; Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany.
  • Feng D; Laboratory of Neurogenetics and.
  • Kim SJ; Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA.
  • Ahmed YA; Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA.
  • Paloczi J; Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA.
  • He Y; Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA, NIH, Bethesda, Maryland, USA.
  • Schuebel K; Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA.
  • Dai S; Laboratory of Neurogenetics and.
  • Liu F; Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA.
  • Pacher P; Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA.
  • Kisseleva T; Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA, NIH, Bethesda, Maryland, USA.
  • Qin X; Department of Surgery, UCSD, San Diego, California, USA.
  • Goldman D; Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA.
  • Tacke F; Laboratory of Neurogenetics and.
  • Gao B; Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany.
J Clin Invest ; 131(9)2021 05 03.
Article en En | MEDLINE | ID: mdl-33724957
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 αvß6 (ITGß6) 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 ITGß6 expression and BEC proliferation. In vitro experiments revealed that bile acid-activated monocytes promoted BEC proliferation through ITGß6. Our data suggest that BEC injury induces cholestasis, monocyte recruitment, and induction of ITGß6, which work together to promote BEC proliferation and therefore represent potential therapeutic targets for cholangiopathies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Biliar / Ácidos y Sales Biliares / Integrinas / Regulación hacia Arriba / Proliferación Celular / Células Epiteliales / Activación de Macrófagos / Macrófagos / Antígenos de Neoplasias Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: J Clin Invest Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Biliar / Ácidos y Sales Biliares / Integrinas / Regulación hacia Arriba / Proliferación Celular / Células Epiteliales / Activación de Macrófagos / Macrófagos / Antígenos de Neoplasias Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: J Clin Invest Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos