P. aeruginosa augments irradiation injury via 15-lipoxygenase–catalyzed generation of 15-HpETE-PE and induction of theft-ferroptosis

Abstract

Total body irradiation (TBI) targets sensitive bone marrow hematopoietic cells and gut epithelial cells causing their death and TBI induces the state of immunodeficiency combined with intestinal dysbiosis and non-productive immune responses. We found enhanced Pseudomonas aeruginosa (PAO1) colonization of the gut leading to the host cell death and strikingly decreased survival of irradiated mice. PAO1-driven pathogenic mechanism includes theft-ferroptosis realized via: i) curbing host anti-ferroptotic system GSH/GPx4 and ii) employing bacterial 15-lipoxygenase (pLoxA) to generate pro-ferroptotic signal -15-hydroperoxy-arachidonoyl-PE (15-HpETE-PE) -in the intestines of irradiated/infected mice. Global redox phospholipidomics of the ileum revealed that lyso-phospholipids and oxidized phospholipids (particularly oxidized phosphatidylethanolamine (PEox) represented the major factors which contributed to the total body irradiation (TBI)+PAO1 induced pathogenic changes. A lipoxygenase inhibitor, baicalein, significantly attenuated animal lethality, PAO1 colonization, as well as intestinal epithelial cell death and generation of ferroptotic PEox signals. Opportunistic PAO1 mechanisms included stimulation of the anti-inflammatory lipoxin A4 (LXA4) production and suppression of the proinflammatory hepoxilin A3 (HxA3) and leukotriene B4 (LTB4). Unearthing complex PAO1 pathogenic/virulence mechanisms including effects on the host anti-/pro-inflammatory responses, lipid metabolism and ferroptotic cell death points to new therapeutic and radiomitigative targets.

The gut microbiota as a booster for radiotherapy: novel insights into radio-protection and radiation injury

“…For example, Pseudomonas aeruginosa , an opportunistic pathogen commonly habituating in hospitalized immunocompromised patients, induces ferroptosis, augments post-radiation gut barrier breach and ensuing lethality through producing 15-lipoxygenase. 15-lipoxygenase also promotes a transition to pro-inflammatory milieu by modulating inflammation-related lipid signaling, immunocyte recruitment and cytokine production in small intestine [ 52 ].…”

Cooperation effects of radiation and ferroptosis on tumor suppression and radiation injury

“…It was proved that Pseudomonas aeruginosa (PAO1) could stimulate ferroptosis by making PAO1 15-lipoxygenase (pLoxA) act on 15-LOX and GPX4 and significantly reduce the survival of irradiated mice. The application of baicalein, a lipoxygenase inhibitor, reversed this phenomenon and reduced mortality in mice exposed to total body irradiation (TBI) and PAO1 infection ( Dar et al, 2022 ). Polycysteine can improve the survival of mice exposed to TBI and reduce radiation-induced damage by activating GPX4 and inhibiting nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) ( Zhang et al, 2021a ).…”

Ferroptosis Is a Potential Therapeutic Target for Pulmonary Infectious Diseases

“…It is shown that NO• produced by macrophages inhibits PA-induced ferroptosis by inhibiting phospholipid peroxidation, especially the production of 15-HOO-AA-PE [76]. Meanwhile, PA generates proferroptotic signal 15-HOO-AA-PE through 15-pLoxA, which suggested that pLoxA inhibitors might be a promising treatment for PA infection [77]. Ferroptosis is a kind of cell death induced by iron-dependent oxidative stress [78].…”