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α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8
David A. Bergin, … , Shane J. O’Neill, Noel G. McElvaney
David A. Bergin, … , Shane J. O’Neill, Noel G. McElvaney
Published November 8, 2010
Citation Information: J Clin Invest. 2010;120(12):4236-4250. https://doi.org/10.1172/JCI41196.
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Research Article Pulmonology Article has an altmetric score of 7

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

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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.

Authors

David A. Bergin, Emer P. Reeves, Paula Meleady, Michael Henry, Oliver J. McElvaney, Tomás P. Carroll, Claire Condron, Sanjay H. Chotirmall, Martin Clynes, Shane J. O’Neill, Noel G. McElvaney

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Figure 6

AAT prevents neutrophil chemotaxis in response to sIC through inhibition of ADAM-17 activity.

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AAT prevents neutrophil chemotaxis in response to sIC through inhibition...
(A) Western blots showing time course of sIC-induced release of FcγRIIIb from MM neutrophils with or without TAPI-1 (10 mM). (B) Quantification of FcγRIIIb release from MM neutrophils treated with sIC (10% v/v) with or without AAT (27.5 mM) (*P < 0.05). Inset: Western blot illustrating FcγRIIIb release at the 10-minute time point. (C) Competitive inhibition of ADAM-17 by AAT. (D) The effect of oxidation (Ox), polymerization (Poly), or the cleaved AAT peptide (C-36 fragment) on TACE inhibition (percent inhibition of maximum activity) was compared with native AAT. *P < 0.05, native AAT or TAPI-1 versus maximal activity; §P = 0.008, polymerized AAT versus native AAT (27.5 mM). (E) Binding of ADAM-17 (250 ng) to immobilized AAT detected in the presence or absence of equimolar concentration of polymerized, C-36 fragment, or native AAT (*P = 0.005). Levels of membrane-bound AAT (F) and FcγRIIIb (G) on isolated resting control MM (green) and ZZ-AATD neutrophils before (red) and 2 days after augmentation therapy (blue). (H) The mean chemotactic index of ZZ-AATD neutrophils (black bars) toward sIC (10% v/v) in serum (50% v/v) was significantly reduced on day 2 when compared with day 0 and with day 7 after augmentation therapy. For comparative analysis, MM neutrophils treated with sIC (white bar) were set at a chemotactic index of 1. Immunoblots in A and B are representative results from 1 of 3 separate experiments. B–E and H are the mean ± SEM of triplicate experiments. F and G are representative results from 1 of 3 separate experiments.

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