IL-1β-Stimulated Bone Mesenchymal Stem Cell-Derived Exosomes Mitigate Sepsis through Modulation of HMGB1/AKT Pathway...

Sepsis is a life-threatening disease caused by infection, and developing novel strategies against sepsis is still required. Exosomes derived from mesenchymal stem cells (MSCs) have shown promising therapeutic potential for various diseases. In this study, we aimed to investigate the action and mechanism of exosomes derived from IL-1β-pre-conditioned bone marrow-derived mesenchymal stromal cells (BMSCs) in sepsis.

Exosomes were isolated from BMSCs that were pretreated with (IL-1β- BMSC/exos) or without IL-1β (BMSC/exos). In vitro, a cell model of sepsis was induced by treating human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS), while in vivo, a sepsis model was established through cecal ligation and puncture (CLP) operation. Immunofluorescence staining was used to detect the uptake of exosomes by HUVECs. The effects of exosomes on the cellular function of HUVECs were determined through EDU proliferation assay, migration assay, and tube formation assay. Gene and protein expression were analyzed using qRT-PCR, Western blot, ELISA, immunofluorescence staining, and immunohistochemistry staining.

IL-1β-BMSC/exos significantly enhanced the proliferation, migration, and tube formation of HUVECs. Treatment with LPS induced the expression of high mobility group box 1 (HMGB1) and the phosphorylation of AKT in HUVECs, but these effects were counteracted by the treatment of IL-1β-BMSC/exos. The protective effect of IL-1β-BMSC/exos on the viability and tube formation ability of HUVECs was reversed by overexpression of HMGB1. Moreover, IL-1β-BMSC/exos promoted the polarization of M2 macrophages and reduced the secretion of inflammatory chemokines. Additionally, IL-1β-BMSC/exos alleviated cecal ligation and puncture (CLP)-induced sepsis in vivo.

IL-1β-BMSC/exos alleviates sepsis by modulating the HMGB1/AKT pathway and triggering M2 macrophage polarization.