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

Cairns, J. T.; Habgood, A.; Edwards-Pritchard, R.; Wilkinson, C.; Stewart, I. D.; Leslie, J.; Blaxall, B. C.; Susztak, K.; Alberti, S.; Nordheim, A.; Oakley, F.; Jenkins, R. G.; Tatler, A. L.

doi:10.1101/755694

bioRxiv · 10.1101/755694

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

Cairns, J. T.·Habgood, A.·Edwards-Pritchard, R.·Wilkinson, C.·Stewart, I. D.·Leslie, J.·Blaxall, B. C.·Susztak, K.·Alberti, S.·Nordheim, A.·Oakley, F.·Jenkins, R. G.·Tatler, A. L.

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Abstract

ETS domain-containing protein-1 (ELK1) is a transcriptional repressor important in regulating v{beta}6 integrin expression. v{beta}6 integrins activate the profibrotic cytokine Transforming Growth Factor {beta}1 (TGF{beta}1) and are increased in the alveolar epithelium in Idiopathic Pulmonary Fibrosis (IPF). IPF is a disease associated with ageing and therefore we hypothesised that aged animals lacking Elk1 globally would develop spontaneous fibrosis in organs where v{beta}6-mediated TGF{beta} activation has been implicated.\n\nHere 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 31, 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 genes 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 cells and murine lung slices to cigarette smoke extract which lead to reduced ELK1 expression which may explain the loss of ELK1 in human disease.\n\nThese 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.

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Cairns, J. T., Habgood, A., Edwards-Pritchard, R., Wilkinson, C., Stewart, I. D., Leslie, J., Blaxall, B. C., Susztak, K., Alberti, S., Nordheim, A., Oakley, F., Jenkins, R. G., Tatler, A. L.. 2019-09-05. Loss of ELK1 has differential effects on age-dependent organ fibrosis and integrin expression. https://doi.org/10.1101/755694

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