α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8.
AuthorsBergin, David A
Reeves, Emer P
McElvaney, Oliver J
Carroll, Tomás P
Chotirmall, Sanjay H
O'Neill, Shane J
McElvaney, Noel G
AffiliationRespiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
alpha 1-Antitrypsin Deficiency
MetadataShow full item record
Citationα-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. 2010, 120 (12):4236-50 J. Clin. Invest.
JournalThe Journal of clinical investigation
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.
- Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase.
- Authors: Jonigk D, Al-Omari M, Maegel L, Müller M, Izykowski N, Hong J, Hong K, Kim SH, Dorsch M, Mahadeva R, Laenger F, Kreipe H, Braun A, Shahaf G, Lewis EC, Welte T, Dinarello CA, Janciauskiene S
- Issue date: 2013 Sep 10
- Do native and polymeric alpha1-antitrypsin activate human neutrophils in vitro?
- Authors: Persson C, Subramaniyam D, Stevens T, Janciauskiene S
- Issue date: 2006 Jun
- The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling.
- Authors: O'Dwyer CA, O'Brien ME, Wormald MR, White MM, Banville N, Hurley K, McCarthy C, McElvaney NG, Reeves EP
- Issue date: 2015 Oct 15
- The effects of weekly augmentation therapy in patients with PiZZ α1-antitrypsin deficiency.
- Authors: Schmid ST, Koepke J, Dresel M, Hattesohl A, Frenzel E, Perez J, Lomas DA, Miranda E, Greulich T, Noeske S, Wencker M, Teschler H, Vogelmeier C, Janciauskiene S, Koczulla AR
- Issue date: 2012
- Alpha-1 antitrypsin augmentation therapy corrects accelerated neutrophil apoptosis in deficient individuals.
- Authors: Hurley K, Lacey N, O'Dwyer CA, Bergin DA, McElvaney OJ, O'Brien ME, McElvaney OF, Reeves EP, McElvaney NG
- Issue date: 2014 Oct 15