Authors
Yue Cao, Zhaoyang Li, Xiangqi Liu, Hefeng Geng, Haotian Zhang, Yeshu Liu, Tianlin Wang, Jingyu Yang
Published in
Archives of pharmacal research. Jun 18, 2026. Epub Jun 18, 2026.
Abstract
Sepsis-associated encephalopathy (SAE), the most common neurological complication of sepsis with high mortality, lacks effective treatments. Although microglia play a significant role in SAE pathogenesis, the mechanisms of M2 microglial exosomes (M2-EXOs) and their microRNAs (miRNAs) remain unclear. The present study demonstrated that both M2 microglial conditioned media (M2-CM) and M2-EXO promote the phenotypic transformation of M1 microglia toward the M2 phenotype. In M2-EXO, among the differentially expressed miRNAs, miR-1949 exhibited the most significant difference. The dual-luciferase assay showed that miR-1949 could bind to the 3'UTR of Dickkopf-related protein 1 (DKK1). Further experiments confirmed that M2-EXO-miR-1949 mimic mediated microglial phenotypic transformation by inhibiting DKK1 and activating the Wnt/β-catenin pathway. Notably, a single injection of M2-EXO (10 μg/mouse, i.c.v.) or M2-EXO-miR-1949 mimic (0.1 nmol/mouse, i.c.v.) significantly reduced the mouse sepsis score (MSS), decreased cortical neural cell damage in SAE mice induced by lipopolysaccharide (LPS), inhibiting abnormal microglial activation and alleviating neuroinflammation. Meanwhile, M2-EXO-miR-1949 mimic markedly inhibited DKK1 and activated the Wnt/β-catenin pathway in vivo. What's more, the effects of M2-EXO-miR-1949 mimic were reversed by the Wnt/β-catenin pathway inhibitor XAV939. In contrast, the effect of M2-EXO-miR-1949 inhibitor (0.1 nmol/mouse, i.c.v.) was opposite to that of M2-EXO-miR-1949 mimic. Furthermore, co-transfection of the M2-EXO-miR-1949 mimic and inhibitor mutually neutralized their opposing effects, resulting in no significant changes in the expression of inflammatory and pathway-related markers, thereby confirming the functional specificity of exosomal miR-1949. In summary, the present study indicates that M2-EXO, especially its contained miR-1949, ameliorates LPS-induced SAE in mice through inhibiting DKK1 to activate the Wnt/β-catenin pathway, thereby leading to microglial phenotypic transformation and neuroinflammation inhibition. This study reveals a novel mechanism by which M2-EXO and miRNA ameliorate SAE, providing a theoretical basis for further studies.
PMID:
42313350
Bibliographic data and abstract were imported from PubMed on 18 Jun 2026.
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