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Dysregulated neutrophil function in individuals with alpha-1 antitrypsin deficiency caused by modified membrane cholesterol content.
BMC Proceedings volume 9, Article number: A7 (2015)
Background
Individuals with alpha-1 antitrypsin (AAT) deficiency (AATD) are predisposed to early-onset emphysema and neutrophils are the primary effector cells responsible for the pathological manifestations of AATD lung disease. As AAT interacts directly with the circulating neutrophil membrane [1], the question that this project addressed was: are AATD neutrophils structurally and functionally altered? The aim of this study was to explore a link between disrupted membrane structure and impaired trafficking of cholesterol in AATD neutrophils.
Methods
Circulating neutrophils were purified from blood of patients with AATD and from healthy control individuals (n=7). Membranes and cytosols were isolated from neutrophils by sucrose-gradient ultracentrifugation. Cholesterol and calcium levels were fluorometric quantified and calpain levels measured using a calpain activity assay. Caveolin-1 expression was examined by Western blot analysis. Statistical comparisons were performed by Student's t-test.
Results
Neutrophil cytosols of AATD individuals had increased calcium concentrations (n=7, p=0.04) and activation of the calcium dependent protease calpain (n=7, p=0.01). Furthermore, levels of the cholesterol trafficking protein caveolin-1 were significantly lower in AATD neutrophil cytosols (n=6, p=0.01) leading to significantly decreased membrane cholesterol content when compared to healthy control cells (n=5, P=0.045).
Conclusions
In summary, our findings have demonstrated for the first time increased calcium, increased calpain activity causing proteolytic cleavage of caveolin-1, and decreased membrane cholesterol content of AATD neutrophils. This novel data may in part explain the dysregulated activity of this innate immune cell in AATD.
References
Bergin D A, et al: alpha-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. J Clin Invest. 120: 4236-4250.
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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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Jundi, B., White, M., Lacey, N. et al. Dysregulated neutrophil function in individuals with alpha-1 antitrypsin deficiency caused by modified membrane cholesterol content.. BMC Proc 9 (Suppl 7), A7 (2015). https://0-doi-org.brum.beds.ac.uk/10.1186/1753-6561-9-S7-A7
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DOI: https://0-doi-org.brum.beds.ac.uk/10.1186/1753-6561-9-S7-A7