IL-1ß-induced mesenchymal stem cell-derived exosomes inhibit neuronal ferroptosis in intracerebral hemorrhage through the HSPA5/GPX4 axis.

ABSTRACT

BACKGROUND: Neuronal cell ferroptosis following intracerebral hemorrhage (ICH) is a crucial factor contributing to the poor prognosis of ICH patients. The objective of this investigation was to investigate the molecular mechanism of IL-1ß-induced mesenchymal stem cell-derived exosomes (IL-1ß-Exo) in mitigating ICH injury. METHODS: Exo and IL-1ß-Exo were obtained and identified. Hemin was used to induce an ICH model, and an ICH mouse model was established using Collagenase. Exo and IL-1ß-Exo interventions were conducted to study their impact and molecular mechanisms on neuronal ferroptosis in ICH. RESULTS: Vesicular structure Exo and IL-1ß-Exo, with an average particle size of 141.7 ± 38.8 nm and 138.8 ± 37.5 nm, respectively, showed high expression of CD63, CD9 and CD81 could be taken up by SH-SY5Y cells. These Exos reversed Hemin-induced abnormalities in neuronal cells, including elevated iron, Fe2+, ROS, MDA, 4-HNE, and decreased SOD, GSH-Px, GSH, FTH1 levels, and cell vitality. The RNA content of IL-1ß-Exo was linked to its ability to reduce iron accumulation. There was an interaction between HSPA5 and GPX4. Exo and IL-1ß-Exo reversed Hemin-induced downregulation of HSPA5 and GPX4 expression. Overexpression and knockdown of HSPA5 respectively potentiate or counteract the impacts of Exo and IL-1ß-Exo. IL-1ß-Exo was more effective than Exo. These findings were further validated in ICH mice. Moreover, both Exo and IL-1ß-Exo reduced the modified neurological severity score and brain water content, as well as alleviated pathological damage in ICH mice. CONCLUSION: IL-1ß-Exo inhibited neuronal ferroptosis in ICH through the HSPA5/GPX4 axis.