Neutrophil extracellular traps mediate m⁶A modification and regulates sepsis-associated acute lung injury by activating ferroptosis in alveolar epithelial cells

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.

Ferroptosis in Macrophage Impairment in Sepsis

“…Cao et al [ 24 ] found that ferroptosis can significantly inhibit IL-1 after LPS induced mouse bone marrow-derived macrophages β , TNF- α , and IL-6, thereby alleviating systemic inflammatory response. Zhang et al [ 25 ] confirmed that ferroptosis can reduce the inflammatory cytokine IL-1 in the mouse model β horizontal effect. Li et al [ 26 ] showed that ferroptosis can reduce the risk of traumatic brain injury in mouse models IL-1 β , TNF- α , and IL-6.…”

An overview of the effects and mechanisms of m6 A methylation on innate immune cells in sepsis

“…Many genetic and epigenetic alternations are related to the maintenance of endothelial function ( 36 ). There is increasing evidence that sepsis-related pulmonary microvascular leakage and organ damage/dysfunction are associated with changes in epigenetics and gene expression ( 37 ). Chemical modification of RNA molecules is crucial for the post-transcriptional regulation of gene expression.…”

“…The generation of neutrophil extracellular traps (NETs) is the main strategy of polymorphonuclear neutrophils (PMN) against microorganisms. NETs are closely related to the pathogenesis of various lung injuries, but relatively little is known about the role of NETs in SA-AKI ( 37 ). Elevated levels of NETs and ferroptosis can be observed in infected ARDS patients and SA-AKI mice.…”

Molecular mechanisms of ferroptosis and relevance to inflammation

“…All these studies suggest that ferroptosis is involved in the development of ALI disease pathology. Ferroptosis may regulate ALI through neutrophil extracellular traps mediate m 6 A modification [122]. The future development of additional drugs or potential targets is essential for the treatment of ALI by targeting ferroptosis.…”