RT Journal Article
SR Electronic
T1 Alpha-1 antitrypsin therapy modulates the neutrophil membrane proteome and secretome
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1901678
DO 10.1183/13993003.01678-2019
A1 Mark P. Murphy
A1 Thomas McEnery
A1 Karen McQuillan
A1 Oisín F. McElvaney
A1 Oliver J. McElvaney
A1 Sarah Landers
A1 Orla Coleman
A1 Anchalin Bussayajirapong
A1 Padraig Hawkins
A1 Michael Henry
A1 Paula Meleady
A1 Emer P. Reeves
A1 Noel G. McElvaney
YR 2020
UL http://erj.ersjournals.com/content/early/2020/02/06/13993003.01678-2019.abstract
AB Obstructive pulmonary disease in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) occurs earlier in life compared to patients without AATD. To understand this further, the aim of this study was to investigate whether AATD presents with altered neutrophil characteristics, due to the specific lack of plasma AAT, compared to non-AATD COPD.This study focused on the neutrophil plasma membrane, and by use of label-free tandem mass spectrometry, the proteome of the neutrophil membrane was compared in FEV1-matched AATD, non-AATD COPD and in AATD patients receiving weekly AAT augmentation therapy (n=6 patients per cohort). Altered protein expression in AATD was confirmed by western blot, ELISA and fluorescence resonance energy transfer analysis.The neutrophil membrane proteome in AATD differed significantly from that of COPD as demonstrated by increased abundance and activity of primary granule proteins including neutrophil elastase on the cell surface in AATD. The signalling mechanism underlying increased degranulation involved Rac2 activation, subsequently resulting in proteinase-activated receptor 2 activation by serine proteinases and enhanced reactive oxygen species production. In vitro and ex vivo, AAT reduced primary granule release and the described plasma membrane variance was resolved post AAT augmentation therapy in vivo, the effects of which significantly altered the AATD neutrophil membrane proteome to that of a non-AATD COPD cell.These results provide strong insight into the mechanism of neutrophil driven airways disease associated with AATD. Therapeutic AAT augmentation modified the membrane proteome to that of a typical COPD cell, with implications for clinical practice.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Murphy has nothing to disclose.Conflict of interest: Dr. McEnery has nothing to disclose.Conflict of interest: Dr. McQuillan has nothing to disclose.Conflict of interest: Dr. McElvaney has nothing to disclose.Conflict of interest: Dr. McElvaney has nothing to disclose.Conflict of interest: Dr. Landers has nothing to disclose.Conflict of interest: Dr. Coleman has nothing to disclose.Conflict of interest: Dr. Bussayajirapong has nothing to disclose.Conflict of interest: Dr. Hawkins has nothing to disclose.Conflict of interest: Dr. Henry has nothing to disclose.Conflict of interest: Dr. Meleady has nothing to disclose.Conflict of interest: Dr. Reeves reports grants from Us Alpha-1 Foundation, during the conduct of the study.Conflict of interest: Dr. McElvaney reports grants from MRCG HRB Funding scheme, during the conduct of the study.