The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche - Centre Eugène Marquis Accéder directement au contenu
Article Dans Une Revue Journal of Pathology Année : 2024

The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche

Ania Alay
  • Fonction : Auteur
Cédric Coulouarn

Résumé

Liver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro-fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (Delta EGFR mice). Here, we have analyzed the response of WT and Delta EGFR mice to chronic treatment with carbon tetrachloride (CCl4), which induces a pro-inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated Delta EGFR mice when compared with CCl4-treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from in vitro experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-fibrotic and pro-inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase-dependent actions in hepatocytes that reveal its key role in chronic liver damage. (c) 2024 The Authors. The Journal of Pathology published by John Wiley and Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Commentaire Datasets: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE265969

Dates et versions

hal-04652471 , version 1 (18-07-2024)

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Ester Gonzalez-Sanchez, Javier Vaquero, Daniel Caballero-Diaz, Jan Grzelak, Noel P. Fuste, et al.. The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche. Journal of Pathology, 2024, 263 (4-5), pp.482-495. ⟨10.1002/path.6299⟩. ⟨hal-04652471⟩
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