Abstract
Neutrophil extracellular traps (NETs) production is a major strategy employed by polymorphonuclear neutrophils (PMNs) to fight against microbes. NETs have been implicated in the pathogenesis of various lung injuries, although few studies have explored NETs in sepsis-associated acute lung injury (SI-ALI). Here, we demonstrate a major contribution of NETs to the pathology of sepsis-associated ALI by inducing ferroptosis of alveolar epithelial cells. Using both in vitro and in vivo studies, our findings show enhanced NETs accumulation in sepsis-associated ALI patients and mice, as well as the closely related upregulation of ferroptosis, the induction of which depends on METTL3-induced m6A modification of GPX4. Using a CLP-induced sepsis-associated ALI mouse model established with METTL3-/- versus WT mice, in addition to METTL3 knockout and overexpression in vitro, we elucidated and confirmed the critical role of ferroptosis in NETs-induced ALI. These findings support a role for NETs-induced METTL3 modification and the subsequent induction of ferroptosis in the pathogenesis of sepsis-associated ALI.
Original language | English (US) |
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Pages (from-to) | 3337-3357 |
Number of pages | 21 |
Journal | International journal of biological sciences |
Volume | 18 |
Issue number | 8 |
DOIs | |
State | Published - 2022 |
Keywords
- ferroptosis
- N6-Methylation
- Neutrophil extracellular traps
- sepsis-associated acute lung injury
ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Applied Microbiology and Biotechnology
- Molecular Biology
- Developmental Biology
- Cell Biology