Increased susceptibility of cystic fibrosis airway epithelial cells to ferroptosis

Biological Research

Murugan Kalimutho¹  David M. Frazer¹  Gregory J. Anderson²  Dora Ling³  Ama-Tawiah Essilfie³  Simon Phipps³  Pramila Maniam³  David W. Reid⁴ 

[1]Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia

[2]Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia

[3]School of Chemistry and Molecular Bioscience, University of Queensland, St Lucia, Australia

[4]Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia

[5]Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia

[6]Adult Cystic Fibrosis Centre, The Prince Charles Hospital, Chermside, Australia

[7]Lung Inflammation and Infection Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, 4003, Herston, QLD, Australia

关键词: Ferroptosis;    Lipid peroxidation;    Erastin;    Iron;    Cystic fibrosis;    Airway epithelial cells;   

DOI  :  10.1186/s40659-021-00361-3

来源: Springer

【 摘 要 】

BackgroundDefective chloride transport in airway epithelial cells (AECs) and the associated lung disease are the main causes of morbidity and early mortality in cystic fibrosis (CF). Abnormal airway iron homeostasis and the presence of lipid peroxidation products, indicative of oxidative stress, are features of CF lung disease.ResultsHere, we report that CF AECs (IB3-1) are susceptible to ferroptosis, a type of cell death associated with iron accumulation and lipid peroxidation. Compared to isogenic CFTR corrected cells (C38), the IB3-1 cells showed increased susceptibility to cell death upon exposure to iron in the form of ferric ammonium citrate (FAC) and the ferroptosis inducer, erastin. This phenotype was accompanied by accumulation of intracellular ferrous iron and lipid peroxides and the extracellular release of malondialdehyde, all indicative of redox stress, and increased levels of lactate dehydrogenase in the culture supernatant, indicating enhanced cell injury. The ferric iron chelator deferoxamine (DFO) and the lipophilic antioxidant ferrostatin-1 inhibited FAC and erastin induced ferroptosis in IB3-1 cells. Glutathione peroxidase 4 (GPX4) expression was decreased in IB3-1 cells treated with FAC and erastin, but was unchanged in C38 AECs. Necroptosis appeared to be involved in the enhanced susceptibility of IB3-1 AECs to ferroptosis, as evidenced by partial cell death rescue with necroptosis inhibitors and enhanced mixed lineage kinase domain-like (MLKL) localisation to the plasma membrane.ConclusionThese studies suggest that the increased susceptibility of CF AECs to ferroptosis is linked to abnormal intracellular ferrous iron accumulation and reduced antioxidant defences. In addition, the process of ferroptotic cell death in CF AECs does not appear to be a single entity and for the first time we describe necroptosis as a potential contributory factor. Iron chelation and antioxidant treatments may be promising therapeutic interventions in cystic fibrosis.Graphical Abstract

【 授权许可】

CC BY