RT Journal Article
T1 Lack of EGFR catalytic activity in hepatocytes improves liver regeneration following DDC‐induced cholestatic injury by promoting a pro‐restorative inflammatory response
A1 Lazcanoiturburu, Nerea
A1 García‐Sáez, Juan
A1 González‐Corralejo, Carlos
A1 Roncero Romero, Cesáreo
A1 Sanz Ortega, Julián
A1 Martín‐Rodríguez, Carlos
A1 Valdecantos, M Pilar
A1 Martínez‐Palacián, Adoración
A1 Almale Del Barrio, Laura
A1 Bragado Domingo, Paloma
A1 Calero‐Pérez, Silvia
A1 Fernández, Almudena
A1 García‐Bravo, María
A1 Guerra, Carmen
A1 Montoliu, Lluis
A1 Segovia, José Carlos
A1 Martínez Valverde, Ángela María
A1 Fabregat Romero, María Isabel
A1 Herrera González, Blanca María
A1 Sánchez Muñoz, Aranzazu
AB 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. © 2022 The Pathological Society of Great Britain and Ireland.
PB Wiley
SN 0022-3417
SN 1096-9896
YR 2022
FD 2022-09-23
LK https://hdl.handle.net/20.500.14352/107028
UL https://hdl.handle.net/20.500.14352/107028
LA eng
NO Lazcanoiturburu, Nerea, et al. «Lack of EGFR Catalytic Activity in Hepatocytes Improves Liver Regeneration Following DDC‐induced Cholestatic Injury by Promoting a Pro‐restorative Inflammatory Response». The Journal of Pathology, vol. 258, n.o 3, noviembre de 2022, pp. 312-24. DOI.org (Crossref), https://doi.org/10.1002/path.6002.
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO European Commission-ERC
DS Docta Complutense
RD 24 jul 2024