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

Hdl Handle:
http://hdl.handle.net/10147/120887
Title:
α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8.
Authors:
Bergin, David A; Reeves, 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.
Citation:
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 investigation
Issue Date:
1-Dec-2010
URI:
http://hdl.handle.net/10147/120887
DOI:
10.1172/JCI41196
PubMed ID:
21060150
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.
Item Type:
Article
Language:
en
Keywords:
GENETICS; RESPIRATORY DISORDER
MeSH:
ADAM Proteins; Antigen-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
ISSN:
1558-8238

Full metadata record

DC FieldValue Language
dc.contributor.authorBergin, David Aen
dc.contributor.authorReeves, Emer Pen
dc.contributor.authorMeleady, Paulaen
dc.contributor.authorHenry, Michaelen
dc.contributor.authorMcElvaney, Oliver Jen
dc.contributor.authorCarroll, Tomás Pen
dc.contributor.authorCondron, Claireen
dc.contributor.authorChotirmall, Sanjay Hen
dc.contributor.authorClynes, Martinen
dc.contributor.authorO'Neill, Shane Jen
dc.contributor.authorMcElvaney, Noel Gen
dc.date.accessioned2011-02-01T16:11:51Z-
dc.date.available2011-02-01T16:11:51Z-
dc.date.issued2010-12-01-
dc.identifier.citationα-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. 2010, 120 (12):4236-50 J. Clin. Invest.en
dc.identifier.issn1558-8238-
dc.identifier.pmid21060150-
dc.identifier.doi10.1172/JCI41196-
dc.identifier.urihttp://hdl.handle.net/10147/120887-
dc.description.abstractHereditary 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.-
dc.language.isoenen
dc.subjectGENETICSen
dc.subjectRESPIRATORY DISORDERen
dc.subject.meshADAM Proteins-
dc.subject.meshAntigen-Antibody Complex-
dc.subject.meshCase-Control Studies-
dc.subject.meshChemotaxis, Leukocyte-
dc.subject.meshGPI-Linked Proteins-
dc.subject.meshHumans-
dc.subject.meshInterleukin-8-
dc.subject.meshMembrane Microdomains-
dc.subject.meshMiddle Aged-
dc.subject.meshModels, Immunological-
dc.subject.meshMutation-
dc.subject.meshNeutrophils-
dc.subject.meshReceptors, IgG-
dc.subject.meshReceptors, Interleukin-8A-
dc.subject.meshRecombinant Proteins-
dc.subject.meshalpha 1-Antitrypsin-
dc.subject.meshalpha 1-Antitrypsin Deficiency-
dc.titleα-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8.en
dc.typeArticleen
dc.contributor.departmentRespiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.en
dc.identifier.journalThe Journal of clinical investigationen

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