Abstract
Eosinophils account for 1–3% of peripheral blood leukocytes and accumulate at sites of allergic inflammation, where they play a pathogenic role. Studies have shown that treatment with mepolizumab (an anti-IL-5 monoclonal antibody) is beneficial to patients with severe eosinophilic asthma, however, the mechanism of precisely how eosinophils mediate these pathogenic effects is uncertain. Eosinophils contain several cationic granule proteins, including Eosinophil Peroxidase (EPO). The main significance of this work is the discovery of EPO as a novel ligand for the HER2 receptor. Following HER2 activation, EPO induces activation of FAK and subsequent activation of β1-integrin, via inside-out signaling. This complex results in downstream activation of ERK1/2 and a sustained up regulation of both MUC4 and the HER2 receptor. These data identify a receptor for one of the eosinophil granule proteins and demonstrate a potential explanation of the proliferative effects of eosinophils.
Highlights
Eosinophils accumulate at local inflammatory sites in allergic conditions such as asthma and allergic rhinitis [1,2,3], where they interact with resident cells including epithelial and nerve cells [4,5,6,7]
A recombinant form of the extracellular domain of HER2 was employed for Surface Plasmon resonance (SPR) studies to ascertain if Eosinophil Peroxidase (EPO) is a ligand for HER2
In this study we have demonstrated that the eosinophil granule protein EPO is a ligand for the HER2 receptor
Summary
Eosinophils accumulate at local inflammatory sites in allergic conditions such as asthma and allergic rhinitis [1,2,3], where they interact with resident cells including epithelial and nerve cells [4,5,6,7]. Eosinophils are implicated in the pathogenesis of disease states such as inflammatory bowel disease [11], rhinitis [12,13], helminth infections [14] and certain epithelial cancers [15] and play a role in non-pathological proliferative conditions such as normal mammary gland development [16]. Eosinophils contain four cationic granule proteins MBP, EDN, ECP and EPO, all of which are toxic at high concentrations to epithelial, muscle and neural cells as well as certain micro-organisms and parasites. Expression levels for each gene were quantified against serial dilutions of purified PCR product
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