MSC-derived exosomal miR-140-3p improves cognitive dysfunction in sepsis-associated encephalopathy by HMGB1 and S-lactoylglutathione metabolism

• Published in: Communications biology Vol. 7; no. 1; pp. 562 - 13
• Main Authors: Ma, Ying, She, Xingguo, Liu, Yang, Qin, Xian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 38/77; 631/378/1934; 631/45/500; 631/532/2074; 631/80/86; 692/699/255; 82/16; 82/58; Animals; Biomedical and Life Sciences; Caspase-1; Cecum; Cognitive ability; Cognitive Dysfunction - etiology; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Disease Models, Animal; Encephalopathy; Exosomes - metabolism; HMGB1 protein; HMGB1 Protein - genetics; HMGB1 Protein - metabolism; Humans; Imipenem; Inflammation; Life Sciences; Male; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Metabolism; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; Nitric-oxide synthase; Pyroptosis; Sepsis; Sepsis - complications; Sepsis - genetics; Sepsis - metabolism; Sepsis-Associated Encephalopathy - genetics; Sepsis-Associated Encephalopathy - metabolism; Therapeutic targets; Tumor necrosis factor-α
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06236-z

MiRNAs in mesenchymal stem cells (MSCs)-derived exosome (MSCs-exo) play an important role in the treatment of sepsis. We explored the mechanism through which MSCs-exo influences cognitive impairment in sepsis-associated encephalopathy (SAE). Here, we show that miR-140-3p targeted Hmgb1 . MSCs-exo plus miR-140-3p mimic (Exo) and antibiotic imipenem/cilastatin (ABX) improve survival, weight, and cognitive impairment in cecal ligation and puncture (CLP) mice. Exo and ABX inhibit high mobility group box 1 (HMGB1), IBA-1, interleukin (IL)-1β, IL-6, iNOS, TNF-α, p65/p-p65, NLRP3, Caspase 1, and GSDMD-N levels. In addition, Exo upregulates S-lactoylglutathione levels in the hippocampus of CLP mice. Our data further demonstrates that Exo and S-lactoylglutathione increase GSH levels in LPS-induced HMC3 cells and decrease LD and GLO2 levels, inhibiting inflammatory responses and pyroptosis. These findings suggest that MSCs-exo-mediated delivery of miR-140-3p ameliorates cognitive impairment in mice with SAE by HMGB1 and S-lactoylglutathione metabolism, providing potential therapeutic targets for the clinical treatment of SAE. MSCs-exo-mediated delivery of miR-1403p ameliorates cognitive impairment in mice with SAE by HMGB1-related microglial pyroptosis and S-lactoylglutathione metabolism.