Induction of ferroptosis-like cell death of eosinophils exerts synergistic effects with glucocorticoids in allergic airway inflammation

Yanping Wu, Haixia Chen, Nanxia Xuan, Lingren Zhou, Yinfang Wu, Chen Zhu, Miao Li, Qingyu Weng, Jiaxin Shen, Hao Zhang, Bin Zhang, Fen Lan, Lixia Xia, Xuefang Xiong, Zhouyang Li, Yun Zhao, Mindan Wu, Songmin Ying, Wen Li, Huahao ShenZhihua Chen

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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.

Original languageEnglish
Pages (from-to)918-927
Number of pages10
JournalThorax
Volume75
Issue number11
DOIs
StatePublished - 1 Nov 2020
Externally publishedYes

Keywords

  • allergic lung disease
  • asthma
  • eosinophil biology

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