Journal Article

microRNA-27b shuttled by mesenchymal stem cell-derived exosomes prevents sepsis by targeting JMJD3 and downregulating NF-κB signaling pathway

Liao, Xin, Sun, Xuan, Wang, Jinsong, Chen, Junhui, Sun, Jia, He, Yixuan, Qiu, Chen, Chen, Rui, Hu, Sean

2021

Overview

Background Exosomal microRNAs (miRs) derived from mesenchymal stem cells (MSCs) have been shown to play roles in the pathophysiological processes of sepsis. Moreover, miR-27b is highly enriched in MSC-derived exosomes. Herein, we aimed to investigate the potential role and downstream molecular mechanism of exosomal miR-27b in sepsis. Methods Inflammation was induced in bone marrow-derived macrophages (BMDMs) by lipopolysaccharide (LPS), and mice were made septic by cecal ligation and puncture (CLP). The expression pattern of miR-27b in MSC-derived exosomes was characterized using RT-qPCR, and its downstream gene was predicted by in silico analysis. The binding affinity between miR-27b, Jumonji D3 (JMJD3), or nuclear factor κB (NF-κB) was characterized to identify the underlying mechanism. We induced miR-27b overexpression or downregulation, along with silencing of JMJD3 or NF-κB to examine their effects on sepsis. The production of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 was detected by ELISA. Results miR-27b was highly expressed in MSC-derived exosomes. Mechanistic investigations showed that miR-27b targeted JMJD3. miR-27b decreased expression of pro-inflammatory genes by inhibiting the recruitment of JMJD3 and NF-κB at gene promoter region. Through this, MSC-derived exosomal miR-27b diminished production of pro-inflammatory cytokines in LPS-treated BMDMs and septic mice, which could be rescued by upregulation of JMJD3 and NF-κB. Besides, in vitro findings were reproduced by in vivo findings. Conclusion These data demonstrated that exosomal miR-27b derived from MSCs inhibited the development of sepsis by downregulating JMJD3 and inactivating the NF-κB signaling pathway.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Abdomen / Adenoviruses / Animals / Antibodies / Biomedical and Life Sciences / Biomedical Engineering and Bioengineering / Bone marrow / Cecum / Cell Biology / Cell culture / Exosome / Exosomes / Exosomes - genetics / Exosomes - metabolism / Flow cytometry / Gene expression / IL-1β / Infections / Inflammation / Interleukin 6 / Jumonji D3 / Jumonji Domain-Containing Histone Demethylases / Laboratory animals / Life Sciences / Lipopolysaccharides / Macrophages / Mesenchymal stem cells / Mesenchymal Stem Cells - metabolism / Mice / MicroRNA-27b / MicroRNAs / MicroRNAs - genetics / miRNA / NF-kappa B - genetics / NF-kappa B - metabolism / NF-κB protein / Nuclear factor κB/p65 / Plasmids / Regenerative Medicine/Tissue Engineering / Sepsis / Sepsis - genetics / Signal Transduction / Stem cell transplantation / Stem Cells / Tumor necrosis factor-α