Eosinophil peroxidase activates cells by HER2 receptor engagement and β1-integrin clustering with downstream MAPK cell signaling.

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.

• Authors: Kerrie Hennigan, Paul J Conroy, Marie-Therese Walsh, Mohamed Amin, Richard O'Kennedy, Patmapriya Ramasamy, Gerald J Gleich, Zeshan Siddiqui, Senan Glynn, Olive McCabe, Catherine Mooney, Brian J Harvey, Richard W Costello, Jean McBryan
• Journal: Clinical immunology (Orlando, Fla.) (Clin Immunol) Vol. 171 Pg. 1-11 (Oct 2016) ISSN: 1521-7035 [Electronic] United States
• PMID: 27519953 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Integrin beta1
• MUC4 protein, human
• Mucin-4
• RNA, Messenger
• RNA, Small Interfering
• Recombinant Proteins
• Eosinophil Peroxidase
• ERBB2 protein, human
• Receptor, ErbB-2
• Focal Adhesion Kinase 1
• PTK2 protein, human
• Extracellular Signal-Regulated MAP Kinases

Topics

• Cell Line
• Eosinophil Peroxidase (genetics, metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Focal Adhesion Kinase 1 (genetics, metabolism)
• Humans
• Integrin beta1 (metabolism)
• Mucin-4 (genetics)
• RNA, Messenger (metabolism)
• RNA, Small Interfering (genetics)
• Receptor, ErbB-2 (genetics, metabolism)
• Recombinant Proteins (metabolism)
• Signal Transduction