IFI27-mediated regulation of regulatory T cells aggravates lung injury in sepsis via IL-10/STAT3 signaling.

Abstract

BACKGROUND AND PURPOSE: Interferon-induced protein 27 (IFI27) is implicated in immune regulation, and regulatory T cells (Tregs) play a critical role in maintaining pulmonary immune homeostasis during sepsis. However, the relationship between IFI27 and Treg-mediated regulation in sepsis-associated lung injury remains unclear. This study aimed to investigate the role of IFI27 in modulating Treg function during sepsis. METHODS: Plasma IFI27 levels were measured in patients with sepsis and healthy controls. mRNA sequencing was performed to assess IFI27 expression profiles., IFI27 expression was examined in a cecal ligation and puncture (CLP) mouse model, and an IFI27 overexpression mouse model was used to evaluate its functional role in sepsis. Immunofluorescence staining and transmission electron microscopy were employed to assess ferroptosis in lung epithelial cells. Flow cytometry was used to analyze Treg populations and their secretion of interleukin-10 (IL-10)., primary Tregs were co-cultured with mouse lung epithelial cells to determine the effects of IFI27 on IL-10 secretion in Tregs and epithelial ferroptosis. Reactive oxygen species (ROS) levels, malondialdehyde (MDA) content, and STAT3 pathway-related protein expression were quantified using ROS assays, MDA measurements, and western blotting, respectively. RESULTS: Clinical analyses demonstrated that plasma IFI27 levels were positively correlated with sepsis severity. IFI27 expression was significantly increased in septic mice. Elevated IFI27 inhibited STAT5 phosphorylation, leading to a reduction in Treg abundance and IL-10 secretion, thereby exacerbating ferroptosis in pulmonary epithelial cells. Furthermore, IFI27 elevation in Tregs increased lipid peroxidation levels by suppressing the IL-10/STAT3 signaling pathway. CONCLUSIONS: These findings indicate that IFI27 is closely associated with sepsis severity and may serve as a potential prognostic indicator. Mechanistically, IFI27 suppresses Treg function and enhances ferroptosis in lung epithelial cells through inhibition of the IL-10/STAT3 signaling pathway, thereby aggravating sepsis-induced lung injury.