TY - JOUR T1 - Loss of ELK1 has differential effects on age-dependent organ fibrosis and integrin expression JF - bioRxiv DO - 10.1101/755694 SP - 755694 AU - Jennifer T Cairns AU - Anthony Habgood AU - Rochelle C Edwards-Pritchard AU - Chloe Wilkinson AU - Iain D Stewart AU - Jack Leslie AU - Burns C Blaxall AU - Katalin Susztak AU - Siegfried Alberti AU - Alfred Nordheim AU - Fiona Oakley AU - R Gisli Jenkins AU - Amanda L Tatler Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/09/05/755694.abstract N2 - ETS domain-containing protein-1 (ELK1) is a transcriptional repressor 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 ageing 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 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.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. ER -