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Loss of ELK1 has differential effects on age-dependent organ fibrosis

Cairns, Jennifer T.; Habgood, Anthony; Edwards-Pritchard, Rochelle C.; Joseph, Chitra; John, Alison E.; Wilkinson, Chloe; Stewart, Iain D.; Leslie, Jack; Blaxall, Burns C.; Sustak, Katalin; Alberti, Siegfried; Nordheim, Alfred; Oakley, Fiona; Jenkins, Gisli; Tatler, Amanda L.

Authors

Jennifer T. Cairns

Anthony Habgood

Rochelle C. Edwards-Pritchard

Chloe Wilkinson

Jack Leslie

Burns C. Blaxall

Katalin Sustak

Siegfried Alberti

Alfred Nordheim

Fiona Oakley

GISLI JENKINS gisli.jenkins@nottingham.ac.uk
Professor of Experimental Medicine



Abstract

© 2019 The Author(s) ETS domain-containing protein-1 (ELK1) is a transcription factor important in regulating αvβ6 integrin expression. αvβ6 integrins activate the profibrotic cytokine Transforming Growth Factor β1 (TGFβ1) and are increased in the alveolar epithelium in idiopathic pulmonary fibrosis (IPF). IPF is a disease associated with aging and therefore we hypothesised that aged animals lacking Elk1 globally would develop spontaneous fibrosis in organs where αvβ6 mediated TGFβ activation has been implicated. Here we identify that Elk1-knockout (Elk1−/0) mice aged to one year developed spontaneous fibrosis in the absence of injury in both the lung and the liver but not in the heart or kidneys. The lungs of Elk1−/0 aged mice demonstrated increased collagen deposition, in particular collagen 3α1, located in small fibrotic foci and thickened alveolar walls. Despite the liver having relatively low global levels of ELK1 expression, Elk1−/0 animals developed hepatosteatosis and fibrosis. The loss of Elk1 also had differential effects on Itgb1, Itgb5 and Itgb6 expression in the four organs potentially explaining the phenotypic differences in these organs. To understand the potential causes of reduced ELK1 in human disease we exposed human lung epithelial cells and murine lung slices to cigarette smoke extract, which lead to reduced ELK1 expression andmay explain the loss of ELK1 in human disease. These data support a fundamental role for ELK1 in protecting against the development of progressive fibrosis via transcriptional regulation of beta integrin subunit genes, and demonstrate that loss of ELK1 can be caused by cigarette smoke.

Journal Article Type Article
Publication Date Mar 1, 2020
Journal The International Journal of Biochemistry & Cell Biology
Print ISSN 1357-2725
Electronic ISSN 1878-5875
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 120
Article Number 105668
APA6 Citation Cairns, J. T., Habgood, A., Edwards-Pritchard, R. C., Joseph, C., John, A. E., Wilkinson, C., …Tatler, A. L. (2020). Loss of ELK1 has differential effects on age-dependent organ fibrosis. International Journal of Biochemistry and Cell Biology, 120, https://doi.org/10.1016/j.biocel.2019.105668
DOI https://doi.org/10.1016/j.biocel.2019.105668
Keywords Cell Biology; Biochemistry
Publisher URL https://www.sciencedirect.com/science/article/pii/S1357272519302456

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