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Neutrophil Membrane Cholesterol Content is a Key Factor in Cystic Fibrosis Lung Disease.
White, Michelle M; Geraghty, Patrick; Hayes, Elaine; Cox, Stephen; Leitch, William; Alfawaz, Bader; Lavelle, Gillian M; McElvaney, Oliver J; Flannery, Ryan; Keenan, Joanne; Meleady, Paula; Henry, Michael; Clynes, Martin; Gunaratnam, Cedric; McElvaney, Noel G; Reeves, Emer P
<p>This article is also available at <a href=""></a></p> <p><strong>BACKGROUND:</strong> Identification of mechanisms promoting neutrophil trafficking to the lungs of patients with cystic fibrosis (CF) is a challenge for next generation therapeutics. Cholesterol, a structural component of neutrophil plasma membranes influences cell adhesion, a key step in transmigration. The effect of chronic inflammation on neutrophil membrane cholesterol content in patients with CF (PWCF) remains unclear. To address this we examined neutrophils of PWCF to evaluate the cause and consequence of altered membrane cholesterol and identified the effects of lung transplantation and ion channel potentiator therapy on the cellular mechanisms responsible for perturbed membrane cholesterol and increased cell adhesion.</p> <p><strong>METHODOLOGY:</strong> PWCF homozygous for the ΔF508 mutation or heterozygous for the G551D mutation were recruited (n=48). Membrane protein expression was investigated by mass spectrometry. The effect of lung transplantation or ivacaftor therapy was assessed by ELISAs, and calcium fluorometric and μ-calpain assays.</p> <p><strong>FINDINGS:</strong> Membranes of CF neutrophils contain less cholesterol, yet increased integrin CD11b expression, and respond to inflammatory induced endoplasmic reticulum (ER) stress by activating μ-calpain. In vivo and in vitro, increased μ-calpain activity resulted in proteolysis of the membrane cholesterol trafficking protein caveolin-1. The critical role of caveolin-1 for adequate membrane cholesterol content was confirmed in caveolin-1 knock-out mice. Lung transplant therapy or treatment of PWCF with ivacaftor, reduced levels of circulating inflammatory mediators and actuated increased caveolin-1 and membrane cholesterol, with concurrent normalized neutrophil adhesion.</p> <p><strong>INTERPRETATION:</strong> Results demonstrate an auxiliary benefit of lung transplant and potentiator therapy, evident by a reduction in circulating inflammation and controlled neutrophil adhesion.</p>
Keyword(s): Cystic Fibrosis; Neutrophils; Cholesterol; Lung Transplant Therapy; Ivacaftor Therapy; Medicine and Health Sciences
Publication Date:
Type: Journal article
Peer-Reviewed: Yes
Institution: Royal College of Surgeons in Ireland
Citation(s): White MW, Geraghty P, Hayes E, Cox S, Leitch W, Alfawaz B, Lavelle GM, McElvaney OJ, Flannery R, Keenan J, Meleady P, Henry M, Clynes M, Gunaratnam C, McElvaney NG, Reeves EP. Neutrophil Membrane Cholesterol Content is a Key Factor in Cystic Fibrosis Lung Disease. EBioMedicine. 2017;23:173-184.
Publisher(s): Elsevier
File Format(s): application/pdf
Related Link(s):
First Indexed: 2017-09-19 07:18:25 Last Updated: 2019-01-31 07:16:26