IL-27 regulates macrophage ferroptosis by inhibiting the Nrf2/HO1 signaling pathway in sepsis-induced ARDS

• Published in: Inflammation research Vol. 74; no. 1; p. 39
• Main Authors: Xiong, Meng, Luo, Renjie, Zhang, Zhijiao, Liu, Panting, Peng, Qiaozhi, Xu, Fang, Guo, Minkang
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2025; Springer Nature B.V
• Subjects: Allergology; Animals; Biomedical and Life Sciences; Biomedicine; Cecum; Dermatology; Ferroptosis; Ferroptosis - drug effects; Heme Oxygenase-1 - metabolism; Immunology; Interleukin 27; Interleukin-27 - pharmacology; Interleukins - pharmacology; Lipopolysaccharides; Lung - pathology; Lungs; Macrophages; Macrophages - drug effects; Macrophages - immunology; Male; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Morbidity; Neurology; NF-E2-Related Factor 2 - metabolism; Oltipraz; Original Research Paper; Pharmacology/Toxicology; Polarization; Proteins; RAW 264.7 Cells; Respiratory distress syndrome; Respiratory Distress Syndrome - etiology; Respiratory Distress Syndrome - immunology; Respiratory Distress Syndrome - metabolism; Rheumatology; Sepsis; Sepsis - complications; Signal transduction; Signal Transduction - drug effects; IL-27; Sepsis; Ferroptosis; Nrf2/HO1; Acute respiratory distress syndrome (ARDS)
• ISSN: 1023-3830; 1420-908X; 1420-908X
• DOI: 10.1007/s00011-024-01986-2

Objectives Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by high morbidity and mortality rates. Sepsis-induced ARDS involves excessive inflammatory responses, which are modulated by macrophages. This study aimed to elucidate the effect of Recombinant Mouse IL-27 Protein on macrophage ferroptosis and polarization, as well as its impact on sepsis-induced ARDS. Methods A cecal ligation and puncture (CLP)-induced sepsis model was established using wild-type (WT) or IL27R −/− mice. Then, the mice were randomly divided into 4 groups: a control group, a CLP group, an IL-27 + CLP combination group, and an IL-27, CLP, and Oltipraz combination group. RAW 264.7 cells and BMDMs were used to further determine the role and mechanism of IL-27 in vitro. Results In vitro, IL-27 alone did not alter the expression of proteins linked to the ferroptosis pathway or macrophage polarization. Contrastingly, the combination of IL-27 with LPS further amplified LPS-induced alterations in the ferroptosis pathway, thereby promoting macrophage M1 polarization and inhibiting M2 polarization. Additionally, IL-27 + LPS increased ROS levels in macrophages. A sepsis-induced ARDS mouse model was then established via CLP. In vivo, IL-27 exacerbated CLP-induced lung injury in WT mice. Additionally, it decreased the expression levels of ferroptosis-related proteins (Nrf2, HO-1, GPX4) and increased those of Ptgs2 in the lung tissue of septic mice. Besides, GSH and SOD levels in lung tissue were also reduced. Moreover, IL-27 also promoted M1 polarization and inhibited M2 polarization in macrophages. In IL27R −/− mice, the effects of IL-27 were abrogated. Oltipraz inhibited IL-27-induced changes by up-regulating Nrf2 expression. Overall, this present study demonstrated that the combination of IL-27 and LPS-induced macrophage ferroptosis, promoted macrophage M1 polarization, and inhibited M2 polarization by inhibiting the Nrf2/HO-1 pathway. Conclusion Oltipraz may alleviate ARDS-related lung injury by up-regulating Nrf2 expression and concurrently inhibiting macrophage ferroptosis.