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Alpha-1 antitrypsin augmentation inhibits proteolysis of neutrophil membrane voltage-gated proton channel-1 in alpha-1 deficient individuals

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posted on 2024-04-25, 17:12 authored by Padraig Hawkins, Julian Sya, Nee Kee Hup, Mark MurphyMark Murphy, Noel G McElvaneyNoel G McElvaney, Emer ReevesEmer Reeves
Background and Objectives: Alpha-1 antitrypsin is a serine protease inhibitor that demonstrates an array of immunomodulatory functions. Individuals with the genetic condition of alpha-1 antitrypsin deficiency (AATD) are at increased risk of early onset emphysematous lung disease. This lung disease is partly driven by neutrophil mediated lung destruction in an environment of low AAT. As peripheral neutrophil hyper-responsiveness in AATD leads to excessive degranulation and increased migration to the airways, we examined the expression of the membrane voltage-gated proton channel-1 (HVCN1), which is integrally linked to neutrophil function. The objectives of this study were to evaluate altered HVCN1 in AATD neutrophils, serine protease-dependent degradation of HVCN1, and to investigate the ability of serum AAT to control HVCN1 expression.
Materials and Methods: Circulating neutrophils were purified from AATD patients (n = 20), AATD patients receiving AAT augmentation therapy (n = 3) and healthy controls (n = 20). HVCN1 neutrophil expression was assessed by flow cytometry and Western blot analysis. Neutrophil membrane bound elastase was measured by fluorescence resonance energy transfer.
Results: In this study we demonstrated that HVCN1 protein is under-expressed in AATD neutrophils (p = 0.02), suggesting a link between reduced HVCN1 expression and AAT deficiency. We have demonstrated that HVCN1 undergoes significant proteolytic degradation in activated neutrophils (p < 0.0001), primarily due to neutrophil elastase activity (p = 0.0004). In addition, the treatment of AATD individuals with AAT augmentation therapy increased neutrophil plasma membrane HVCN1 expression (p = 0.01).
Conclusions: Our results demonstrate reduced levels of HVCN1 in peripheral blood neutrophils that may influence the neutrophil-dominated immune response in the AATD airways and highlights the role of antiprotease treatment and specifically AAT augmentation therapy in protecting neutrophil membrane expression of HVCN1.

Funding

Medical Research Charities Group/Health Research Board Joint Funding Scheme (MRCG2018-04)

Wellcome Trust Vacation Scholarship

History

Comments

The original article is available at https://www.mdpi.com/

Published Citation

Hawkins P. et al. Alpha-1 antitrypsin augmentation inhibits proteolysis of neutrophil membrane voltage-gated proton channel-1 in alpha-1 deficient individuals. Medicina (Kaunas). 2021;57(8):814.

Publication Date

10 August 2021

PubMed ID

34441020

Department/Unit

  • Beaumont Hospital
  • Medicine
  • Undergraduate Research

Publisher

MDPI

Version

  • Published Version (Version of Record)