IL-1β-pretreated bone mesenchymal stem cell-derived exosomes alleviate septic endoplasmic reticulum stress via regulating SIRT1/ERK pathway.

Background: Endoplasmic reticulum (ER) plays a crucial role in the development of organ injury caused by sepsis. Therefore, it is highly important to devise strategies that specially target ER stress for the treatment of sepsis. Previous research has shown that priming chemokines can enhance the therapeutic effects of mesenchymal stem cells (MSCs). In this study, we aimed to investigate the function and mechanism of exosomes derived from MSCs that were pretreated with IL-1β (IB-exos) in the context of septic ER stress. Methods: Mouse bone MSCs were preconditioned with or without IL-1β and the supernatant was used for exosome extraction. In vitro sepsis cell mode was induced by treating HUVECs with LPS, while in vivo sepsis model was established through cecal ligation and puncture (CLP) operation in mice. Cell viability, apoptosis, motility, and tube formation were assessed using the EDU proliferation assay, flow cytometry analysis, migration assay, and tube formation assay, respectively. The molecular mechanism was investigated using ELISA, qRT-PCR, Western blot, and immunofluorescence staining. Results: Pretreatment with IL-1β enhanced the positive impact of MSC-exos on the viability, apoptosis, motility, and tube formation ability of HUVECs. The administration of LPS or CLP increased ER stress response, but this effect was blocked by the treatment of IB-exos. Additionally, IB-exos reversed the inhibitory effects of LPS or CLP on the expression levels of SIRT1 and ERK phosphorylation. Knockdown of SIRT1 counteracted the effects of IB-exos on HUVEC cellular function and ER stress. In a mouse model, the injection of IB-exos mitigated sepsis-induced lung injury by inhibiting ER stress response through the activation of SIRT1. Conclusion: IB-exos have been found to alleviate sepsis-induced lung injury via inhibiting ER stress through the SIRT1/ERK pathway. These findings indicated that IB-exos could potentially be used as a strategy to mitigate lung injury caused by sepsis.