Type

Journal Article

Authors

Noel G McElvaney
Shane J O'Neill
Martin Clynes
Sanjay H Chotirmall
Claire Condron
Tomás P Carroll
Oliver J McElvaney
Michael Henry
Paula Meleady
Emer P Reeves
and 1 others

Subjects

Biochemistry

Topics
genetics neutrophils alpha 1 antitrypsin membrane microdomains drug therapy adam proteins models immunological fcgr3b protein human gpi linked proteins antigen antibody complex mutation case control studies chemotaxis leukocyte interleukin 8 middle aged il8 protein human pharmacology tumor necrosis factor alpha convertase receptors interleukin 8a alpha 1 antitrypsin deficiency metabolism humans immunology recombinant proteins receptors igg drug effects

α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. (2009)

Abstract 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.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Noel G McElvaney, Shane J O'Neill, Martin Clynes, Sanjay H Chotirmall, Claire Condron, Tomás P Carroll, Oliver J McElvaney, Michael Henry, Paula Meleady, Emer P Reeves and 1 others

Experts in our system

1
Noel G McElvaney
Royal College of Surgeons in Ireland
Total Publications: 190
 
2
Shane J O'Neill
Royal College of Surgeons in Ireland
Total Publications: 83
 
3
Martin Clynes
Dublin City University
Total Publications: 209
 
4
Sanjay H Chotirmall
Royal College of Surgeons in Ireland
Total Publications: 22
 
5
Tomás P Carroll
Royal College of Surgeons in Ireland
Total Publications: 25
 
6
Oliver J McElvaney
Royal College of Surgeons in Ireland
 
7
Michael Henry
Dublin City University
Total Publications: 78
 
8
Paula Meleady
Dublin City University
Total Publications: 95
 
9
Emer P Reeves
Royal College of Surgeons in Ireland
Total Publications: 58