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

Ying Ma; Xingguo She; Yang Liu; Xian Qin

doi:10.1038/s42003-024-06236-z

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.

Authors

Ying Ma¹, Xingguo She¹, Yang Liu², Xian Qin³

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. qinxian@csu.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cognitive Dysfunction* / etiology
Cognitive Dysfunction* / genetics
Cognitive Dysfunction* / metabolism
Disease Models, Animal
Exosomes* / metabolism
HMGB1 Protein* / genetics
HMGB1 Protein* / metabolism
Humans
Male
Mesenchymal Stem Cells* / metabolism
Mice
Mice, Inbred C57BL
MicroRNAs* / genetics
MicroRNAs* / metabolism
Sepsis / complications
Sepsis / genetics
Sepsis / metabolism
Sepsis-Associated Encephalopathy* / genetics
Sepsis-Associated Encephalopathy* / metabolism

Substances

MicroRNAs
HMGB1 Protein
HMGB1 protein, mouse
Mirn140 microRNA, human