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Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium
Haider H. Dar, … , Hülya Bayır, Valerian E. Kagan
Haider H. Dar, … , Hülya Bayır, Valerian E. Kagan
Published September 10, 2018
Citation Information: J Clin Invest. 2018;128(10):4639-4653. https://doi.org/10.1172/JCI99490.
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Research Article Cell biology Infectious disease Article has an altmetric score of 13

Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium

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Abstract

Ferroptosis is a death program executed via selective oxidation of arachidonic acid–phosphatidylethanolamines (AA-PE) by 15-lipoxygenases. In mammalian cells and tissues, ferroptosis has been pathogenically associated with brain, kidney, and liver injury/diseases. We discovered that a prokaryotic bacterium, Pseudomonas aeruginosa, that does not contain AA-PE can express lipoxygenase (pLoxA), oxidize host AA-PE to 15-hydroperoxy-AA-PE (15-HOO-AA-PE), and trigger ferroptosis in human bronchial epithelial cells. Induction of ferroptosis by clinical P. aeruginosa isolates from patients with persistent lower respiratory tract infections was dependent on the level and enzymatic activity of pLoxA. Redox phospholipidomics revealed elevated levels of oxidized AA-PE in airway tissues from patients with cystic fibrosis (CF) but not with emphysema or CF without P. aeruginosa. We believe that the evolutionarily conserved mechanism of pLoxA-driven ferroptosis may represent a potential therapeutic target against P. aeruginosa–associated diseases such as CF and persistent lower respiratory tract infections.

Authors

Haider H. Dar, Yulia Y. Tyurina, Karolina Mikulska-Ruminska, Indira Shrivastava, Hsiu-Chi Ting, Vladimir A. Tyurin, James Krieger, Claudette M. St. Croix, Simon Watkins, Erkan Bayir, Gaowei Mao, Catherine R. Armbruster, Alexandr Kapralov, Hong Wang, Matthew R. Parsek, Tamil S. Anthonymuthu, Abiola F. Ogunsola, Becca A. Flitter, Cody J. Freedman, Jordan R. Gaston, Theodore R. Holman, Joseph M. Pilewski, Joel S. Greenberger, Rama K. Mallampalli, Yohei Doi, Janet S. Lee, Ivet Bahar, Jennifer M. Bomberger, Hülya Bayır, Valerian E. Kagan

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Figure 5

Redox phospholipidomics reveals pro-ferroptotic oxygenated PE species in airway tissue samples from patients with CF.

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Redox phospholipidomics reveals pro-ferroptotic oxygenated PE species in...
(A) Volcano plot of differences in the levels of PEox species in CF vs. non-CF patients — log2(fold difference) vs. significance [–log10 (P value)]. Airway tissues from patients with emphysema were used as controls. Yellow, red, blue, and black circles represent PEox species containing 1, 2, 3, and 4 oxygens, respectively. n = 10 (B) Quantitative assessments of PEox species. Non-CF samples (n = 10), CF samples with P. aeruginosa (PA; n = 6), CF samples with other bacterial pathogens (B. cenocepacia or A. xylosoxidans and M. abscessus, n = 4). (C–E) MS/MS-based identification of PEox molecular species in samples from patients with CF. Typical MS/MS spectra of PEox precursors with m/z 738.5 (PE16:0/20:4) (C) and 736.5 (PE16:1/20:4) (D) containing AA (C20:4 at m/z 303.2) at sn-2 positions. MS/MS spectra of PEox with m/z 770.5 (PE16:0/20:4+2O) containing oxygenated AA (C20:4+2O at m/z 335.2) (E) formed from the PE species with m/z 738.5 plus 2 oxygens (of 3 performed). (F) Tobramycin-resistant P. aeruginosa clinical isolates (TRPA002–TRPA122) from patients with persistent lower respiratory infection induce ferroptosis. Biofilm supernatants from P. aeruginosa isolates incubated with HBE cells with or without ferrostatin-1 (0.2 μM). Ferroptosis was calculated by subtracting from cell death induced by supernatants the cell death in the presence of ferrostatin-1. Ferroptotic activity of clinical isolates correlated significantly with pLoxA amounts (determined by Western blotting; n = 29) (G, left panel), displayed strong positive dependence on 15LOX activity (G, middle panel) (P ≤ 0.0036), and correlated negatively with the GSH level of HBE cells after treatment (G, right panel). (H) 3D plot illustrating jointly predicted ferroptotic activity of 15LOX activity and GSH (n = 29). n is number of samples. One-way ANOVA.

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