Date of Award
MSc by research (Master of Science by research)
Professor Richard Costello
Asthma, Rhinitis, Eosinophils, Epithelial Cells
Eosinophils account for 1 - 3% of peripheral blood leukocytes and accumulate a local inflammatory sites in allergic conditions such as asthma and allergic rhinitis. Eosinophils contain four cationic granule proteins, Eosinophil Peroxidase (EPO), Eosinophil Derived Neurotoxin (EDN), Eosinophil Cationic Protein (ECP) and Major Basic Protein (MBP) and all are highly toxic at high concentration. However, these eosinophil granule proteins exhibit positive effects at a lower, more physiological concentration, such as cell and tissue remodelling and growth factor receptor expression. Eosinophils localise to epithelial cells in vivo and this study looks at the effect of eosinophil granule proteins on human bronchial epithelial cells.
In this study, we present evidence that EPO forms a complex with and activates the HER2 receptor, with consequent upregulation of HER2 receptor expression. This EPO-HER2 interaction is dependent on N-linked glycosylation. We also provide evidence that, subsequent to HER2 activation, EPO induces activation of pi integrin, activation of FAK and activation of ERK. The activation of FAK and p1 integrin is dependent on the initial activation of the HER2 receptor. The activation of FAK is independent of pi-integrin activation and the activation of ERK is delayed in the absence of pi integrin activation. We also found an EPOinduced, HER2-dependent upregulation of MUC4 at a transcriptional level.
These results suggest that eosinophil localisation to epithelial cells, as seen in asthma and rhinitis, induces growth factor receptor expression and activation of subsequent downstream pathways associated with cell proliferation, all of which are necessary for the airway to repair and remodel after an inflammatory episode. EPO-induced upregulation of MUC4 gene expression indicates that eosinophils may also contribute to increased mucociliary clearance during an inflammatory attack.
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Hennigan K. Eosinophil peroxidase engages the HER2 receptor and induces integrin clustering with downstream signalling consequences. [MSc Thesis]. Dublin: Royal College of Surgeons in Ireland; 2011.