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

  • Commun Biol. 2024 May 11;7(1):562. doi: 10.1038/s42003-024-06236-z.
Ying Ma  1 ,  Xingguo She  1 ,  Yang Liu  2 ,  Xian Qin  3
Affiliations
  • 1. Department of Transplant Surgery, The Third Xiangya Hospital, Central South University, 410013, Changsha, China.
  • 2. Department of Pathology, The Third Xiangya Hospital, Central South University, 410013, Changsha, China.
  • 3. Department of Gynaecology, The Third Xiangya Hospital, Central South University, 410013, Changsha, China. [email protected].
PMID: 38734709 DOI: 10.1038/s42003-024-06236-z
Abstract

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.

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