Induction of ferroptosis-like cell death of eosinophils exerts synergistic effects with glucocorticoids in allergic airway inflammation
- 5 August 2020
- Vol. 75 (11), 918-927
- https://doi.org/10.1136/thoraxjnl-2020-214764
Abstract
Introduction Eosinophils are critical in allergic disorders, and promoting eosinophil death effectively attenuates allergic airway inflammation. Ferroptosis is a recently described novel form of cell death; however, little is known about ferroptosis in eosinophils and related diseases. This study aimed to investigate the effects of ferroptosis-inducing agents (FINs) on eosinophil death and allergic airway inflammation, and to explore their potential synergistic effect with glucocorticoids (GCs). Methods Eosinophils isolated from the peripheral blood of humans or mice were incubated with FINs, and eosinophil ferroptosis was assessed. The in vivo effects of FINs alone or in combination with dexamethasone (DXMS) were examined in a mouse model of allergic airway inflammation. Bronchoalveolar lavage fluid and lung tissue were collected to examine airway inflammation. Results Treatment with FINs time and dose dependency induced cell death in human and mouse eosinophils. Interestingly, FINs induced non-canonical ferroptosis in eosinophils, which generated morphological characteristics unique to ferroptosis and was iron dependent but was independent of lipid peroxidation. The antioxidants glutathione and N-acetylcysteine significantly attenuated FIN-induced cell death. Treatment with FINs triggered eosinophil death in vivo and eventually relieved eosinophilic airway inflammation in mice. Furthermore, FINs exerted a synergistic effect with DXMS to induce eosinophil death in vitro and to alleviate allergic airway inflammation in vivo. Conclusions FINs induced ferroptosis-like cell death of eosinophils, suggesting their use as a promising therapeutic strategy for eosinophilic airway inflammation, especially due to the advantage of their synergy with GCs in the treatment of allergic disorders.Keywords
This publication has 38 references indexed in Scilit:
- The role of iron and reactive oxygen species in cell deathNature Chemical Biology, 2013
- Eosinophil Apoptosis as a Therapeutic Target in Allergic AsthmaBasic & Clinical Pharmacology & Toxicology, 2013
- Living and dying for inflammation: neutrophils, eosinophils, basophilsTrends in Immunology, 2013
- Targeting eosinophils in allergy, inflammation and beyondNature Reviews Drug Discovery, 2013
- Eosinophils: changing perspectives in health and diseaseNature Reviews Immunology, 2012
- Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell DeathCell, 2012
- Targeting Eosinophil Biology in Asthma TherapyAmerican Journal of Respiratory Cell and Molecular Biology, 2011
- Eosinophils: Biological Properties and Role in Health and DiseaseClinical and Experimental Allergy, 2008
- Synthetic Lethal Screening Identifies Compounds Activating Iron-Dependent, Nonapoptotic Cell Death in Oncogenic-RAS-Harboring Cancer CellsCell Chemical Biology, 2008
- Glucocorticoids and AsthmaPublished by Springer Science and Business Media LLC ,2002