α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8.
Authors
Bergin, David AReeves, Emer P
Meleady, Paula
Henry, Michael
McElvaney, Oliver J
Carroll, Tomás P
Condron, Claire
Chotirmall, Sanjay H
Clynes, Martin
O'Neill, Shane J
McElvaney, Noel G
Affiliation
Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.Issue Date
2010-12-01Keywords
GENETICSRESPIRATORY DISORDER
MeSH
ADAM ProteinsAntigen-Antibody Complex
Case-Control Studies
Chemotaxis, Leukocyte
GPI-Linked Proteins
Humans
Interleukin-8
Membrane Microdomains
Middle Aged
Models, Immunological
Mutation
Neutrophils
Receptors, IgG
Receptors, Interleukin-8A
Recombinant Proteins
alpha 1-Antitrypsin
alpha 1-Antitrypsin Deficiency
Metadata
Show full item recordCitation
α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. 2010, 120 (12):4236-50 J. Clin. Invest.Journal
The Journal of clinical investigationDOI
10.1172/JCI41196PubMed ID
21060150Abstract
Hereditary deficiency of the protein α-1 antitrypsin (AAT) causes a chronic lung disease in humans that is characterized by excessive mobilization of neutrophils into the lung. However, the reason for the increased neutrophil burden has not been fully elucidated. In this study we have demonstrated using human neutrophils that serum AAT coordinates both CXCR1- and soluble immune complex (sIC) receptor-mediated chemotaxis by divergent pathways. We demonstrated that glycosylated AAT can bind to IL-8 (a ligand for CXCR1) and that AAT-IL-8 complex formation prevented IL-8 interaction with CXCR1. Second, AAT modulated neutrophil chemotaxis in response to sIC by controlling membrane expression of the glycosylphosphatidylinositol-anchored (GPI-anchored) Fc receptor FcγRIIIb. This process was mediated through inhibition of ADAM-17 enzymatic activity. Neutrophils isolated from clinically stable AAT-deficient patients were characterized by low membrane expression of FcγRIIIb and increased chemotaxis in response to IL-8 and sIC. Treatment of AAT-deficient individuals with AAT augmentation therapy resulted in increased AAT binding to IL-8, increased AAT binding to the neutrophil membrane, decreased FcγRIIIb release from the neutrophil membrane, and normalization of chemotaxis. These results provide new insight into the mechanism underlying the effect of AAT augmentation therapy in the pulmonary disease associated with AAT deficiency.Item Type
ArticleLanguage
enISSN
1558-8238ae974a485f413a2113503eed53cd6c53
10.1172/JCI41196