P. aeruginosa Induced Lipid Peroxidation Causes Ferroptotic Cell Death in Airways

Abstract

BACKGROUND/AIMS: Oxidative stress and infections by Pseudomonas aeruginosa (P. aeruginosa) are prominent in lungs of patients suffering from cystic fibrosis (CF). METHODS: The present study examines effects of P. aeruginosa on lipid peroxidation in human and mouse lungs, and cell death induced by P. aeruginosa in human airway epithelial cells. The role of the Ca2+ activated Cl- channel TMEM16A, the phospholipid scramblase TMEM16F, and the CFTR Cl- channel for ferroptotic cell death is examined. RESULTS: Lipid peroxidation was detected in human CF lungs, which correlated with bacterial infection. In vivo inoculation with P. aeruginosa or Staphylococcus aureus (S. aureus) induced lipid peroxidation in lungs of mice lacking expression of CFTR, and in lungs of wild type animals. Incubation of CFBE human airway epithelial cells with P. aeruginosa induced an increase in reactive oxygen species (ROS), causing lipid peroxidation and cell death independent of expression of wt-CFTR or F508del-CFTR. Knockdown of TMEM16A attenuated P. aeruginosa induced cell death. Antioxidants such as coenzyme Q10 and idebenone as well as the inhibitor of ferroptosis, ferrostatin-1, inhibited P. aeruginosa-induced cell death. CFBE cells expressing wtCFTR, but not F508del-CFTR, activated a basal Cl- conductance upon exposure to P. aeruginosa, which was caused by an increase in intracellular basal Ca2+ concentrations and activation of Ca2+-dependent adenylate cyclase. CONCLUSION: The data suggest an intrinsic pro-inflammatory phenotype in CF epithelial cells, while ferroptosis is observed in both non-CF and CF epithelial cells upon infection with P. aeruginosa. CF cells fail to activate fluid secretion in response to infection with P. aeruginosa. The use of antioxidants and inhibitors of ferroptosis is proposed as a treatment of pneumonia caused by infection with P. aeruginosa.

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

“…In addition to manipulation of host lipid mediator–driven responses, recent studies have identified exploitation of host lipid peroxidation pathways as a virulence strategy of PAO1 ( 12 , 43 , 44 ). The process of ferroptosis is driven by peroxidation of PUFA-phospholipids and accumulation of unstable hydroperoxy-phospholipids — which can be cleaved to toxic levels of oxidatively truncated electrophilic products attacking nucleophilic sites in target proteins — if the regulatory reduced glutathione (GSH)/GPx4 system fails to reduce them to the more stable alcohols ( 11 , 45 ).…”

“…aeruginosa has been supported by 2 recent independent studies, by Bagayoko et al and Ousingsawat et al, which also highlighted and documented the critical role of P . aeruginosa induced ferroptosis in the pathology of pneumonia and cystic fibrosis ( 43 , 44 ). Here, by using a lipoxygenase inhibitor, baicalein, we demonstrate that this increased lethality of PAO1 infection after irradiation is due, at least in part, to pLoxA-stimulated ferroptosis.…”

NLRP3 inflammasome activation in cigarette smoke priming for Pseudomonas aeruginosa-induced acute lung injury

“…Our data suggest that neutrophil infiltration and lung cell apoptosis or necroptosis may not be important contributors to CS primed P. aeruginosa -triggered ALI. P. aeruginosa has recently been shown to induce lipid peroxidation, leading to ferroptotic cell death in human airway epithelial cells [ [43] , [44] , [45] ]. Future studies are needed to address if lipid peroxidation and ferroptotic cell death contributes to CS priming PA-triggered ALI.…”

Ferroptosis: A mixed blessing for infectious diseases

“…Oxidative stress caused by P. aeruginosa is one of the most important causes of cystic fibrosis in the human lung as P. aeruginosa can elevate ROS in cystic fibrosis airway epithelial cells. This could lead to lipid peroxidation and ultimately trigger ferroptosis, while Fer-1 and other ferroptosis inhibitors could improve the pathological condition of the diseased airway ( Ousingsawat et al, 2021 ), implicating that the inhibition of ferroptosis was of great significance in the treatment of P. aeruginosa.…”