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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 7

AAT binds IL-8 and modulates neutrophil chemotaxis by controlling CXCR1 binding.

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AAT binds IL-8 and modulates neutrophil chemotaxis by controlling CXCR1 ...
(A) Binding of IL-8 (10 ng) to immobilized CXCR1 was inhibited in the presence of AAT (27.5 mM) (*P = 0.002). (B) Comparative binding of IL-8 to AAT and HSA. AAT (27.5 mM) bound approximately 20 ng IL-8. (C) Comparative binding of IL-8 to serum purified AAT and recombinant non-glycosylated (Rec non-glycos) AAT (*P = 0.001). (D) Expression levels of phospho-Akt Ser473 after IL-8 (1 ng/1 × 107 cells) treatment. Wortmannin (Wort, 100 nM) and AAT (27.5 mM), but not HSA, inhibited Akt activity efficiently (*P < 0.05 versus IL-8 control). (E) AAT (27.5 mM) significantly inhibited phosphorylation of Akt induced by 10 ng and 20 ng IL-8 (*P < 0.05 versus IL-8 control). (F) Time course of changes in Ca2+ intensity in response to IL-8 (10 ng) with or without AAT (27.5 mM). (G) AAT suppression of IL-8–induced actin cytoskeletal rearrangements. Immunoblot with anti-actin antibody for the distribution of G-actin (in the supernatant fraction [S]) and F-actin (in the pellet fraction [P]) in untreated or AAT-treated (27.5 mM) cells (top panel). Lower panel: IL-8–treated (10 ng) MM neutrophils with or without AAT or control Wort (100 nM). Distribution ratios are shown. (H) Confocal images of neutrophils (MM) undergoing chemotaxis in response to IL-8 (10 ng). F-actin at the leading edge of neutrophils (arrows) was not apparent in resting cells (Un) or cells treated with IL-8 plus AAT (27.5 mM) (×40 magnification, ×10 zoom). (I) IL-8–induced (10 ng) mean chemotactic index of ZZ-AATD neutrophils (black bars) on day 2 after therapy compared with day 0 and with day 7 after augmentation therapy. All experiments were performed in triplicate on 3 consecutive days, and each measurement is the mean ± SEM. Images in D-H are representative results of 1 of 3 separate experiments.

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