(Institución)
 
 

Docu-menta > Investigación Básica > Artículos de Investigación Básica >

Por favor, use este identificador para citar o enlazar este ítem: http://documenta.ciemat.es/handle/123456789/2356

Título : Lack of EGFR catalytic activity in hepatocytes improves liver regeneration following DDC-induced cholestatic injury by promoting a pro-restorative inflammatory response
Autor : Lazcanoiturburu, Nerea
García-Sáez, Juan
González-Corralejo, Carlos
Roncero, Cesáreo
Sanz, Julián
Martín-Rodríguez, Carlos
Valdecantos, M Pilar
Martínez-Palacián, Adoración
Almalé, Laura
Bragado, Paloma
Calero-Pérez, Silvia
Fernández, Almudena
García-Bravo, María
Guerra, Carmen
Montoliu, Lluis
Segovia, José Carlos
Valverde, Ángela M
Fabregat, Isabel
Herrera, Blanca
Sánchez, Arancha
Fecha de publicación : nov-2022
Editorial : Journal of Pathology
Citación : Lazcanoiturburu N, García-Sáez J, González-Corralejo C, Roncero C, Sanz J, Martín-Rodríguez C, Valdecantos MP, Martínez-Palacián A, Almalé L, Bragado P, Calero-Pérez S, Fernández A, García-Bravo M, Guerra C, Montoliu L, Segovia JC, Valverde ÁM, Fabregat I, Herrera B, Sánchez A. Lack of EGFR catalytic activity in hepatocytes improves liver regeneration following DDC-induced cholestatic injury by promoting a pro-restorative inflammatory response. J Pathol. 2022 Nov;258(3):312-324. doi: 10.1002/path.6002. Epub 2022 Sep 23. PMID: 36148647.
Resumen : Despite the well-known hepatoprotective role of the epidermal growth factor receptor (EGFR) pathway upon acute damage, its specific actions during chronic liver disease, particularly cholestatic injury, remain ambiguous and unresolved. Here, we analyzed the consequences of inactivating EGFR signaling in the liver on the regenerative response following cholestatic injury. For that, transgenic mice overexpressing a dominant negative mutant human EGFR lacking tyrosine kinase activity (ΔEGFR) in albumin-positive cells were submitted to liver damage induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), an experimental model resembling human primary sclerosing cholangitis. Our results show an early activation of EGFR after 1-2 days of a DDC-supplemented diet, followed by a signaling switch-off. Furthermore, ΔEGFR mice showed less liver damage and a more efficient regeneration following DDC injury. Analysis of the mechanisms driving this effect revealed an enhanced activation of mitogenic/survival signals, AKT and ERK1/2-MAPKs, and changes in cell turnover consistent with a quicker resolution of damage in response to DDC. These changes were concomitant with profound differences in the profile of intrahepatic immune cells, consisting of a shift in the M1/M2 balance towards M2 polarity, and the Cd4/Cd8 ratio in favor of Cd4 lymphocytes, overall supporting an immune cell switch into a pro-restorative phenotype. Interestingly, ΔEGFR livers also displayed an amplified ductular reaction, with increased expression of EPCAM and an increased number of CK19-positive ductular structures in portal areas, demonstrating an overexpansion of ductular progenitor cells. In summary, our work supports the notion that hepatocyte-specific EGFR activity acts as a key player in the crosstalk between parenchymal and non-parenchymal hepatic cells, promoting the pro-inflammatory response activated during cholestatic injury and therefore contributing to the pathogenesis of cholestatic liver disease.
URI : http://documenta.ciemat.es/handle/123456789/2356
Aparece en las colecciones: Artículos de Investigación Básica

Ficheros en este ítem:

Fichero Descripción Tamaño Formato
Lazcanoiturburu-J PATHOL 2022.pdf15.49 MBAdobe PDFVisualizar/Abrir
View Statistics

Los ítems de Docu-menta están protegidos por una Licencia Creative Commons, con derechos reservados.

 

Información y consultas: documenta@ciemat.es | Documento legal