Abstract
BackgroundExosomal 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.MethodsInflammation 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.ResultsmiR-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.ConclusionThese data demonstrated that exosomal miR-27b derived from MSCs inhibited the development of sepsis by downregulating JMJD3 and inactivating the NF-κB signaling pathway.
Highlights
Exosomal microRNAs derived from mesenchymal stem cells (MSCs) have been shown to play roles in the pathophysiological processes of sepsis
Exosomes were isolated from the supernatants of mouse MSCs (MSC-EXO) and mouse fibroblasts L929 (L929-EXO) and examined by transmission electron microscopy (TEM) and Nanoparticle tracking analysis (NTA) (Fig. 1b, c)
The expression of miR-27b in MSC-derived exosomes (MSC-EXO) and L929-EXO was quantified by Reverse transcription quantitative polymerase chain reaction (RT-qPCR), and the results of which showed that miR27b was highly expressed in MSC-EXO compared to L929 control (p < 0.05; Fig. 1d)
Summary
Exosomal microRNAs (miRs) derived from mesenchymal stem cells (MSCs) have been shown to play roles in the pathophysiological processes of sepsis. We aimed to investigate the potential role and downstream molecular mechanism of exosomal miR-27b in sepsis. Sepsis is characterized by life-threatening organ dysfunction attributed to a dysregulated widespread activation of host response to infection, which is known as systemic inflammatory response syndrome, leading to large human morbidity and mortality rates each year [2, 3]. Sepsis can trigger complex interactions between the proinflammatory and anti-inflammatory processes of the host. A better understanding of inflammatory responseassociated mechanisms will provide a new therapeutic approach for the treatment of sepsis [4]. Because therapeutic regimens to ameliorate sepsis are not available, infection is mainly controlled through source control, antibiotics, and organ function support [5]. Identification of biomarkers based on the molecular mechanism underlying sepsis is important to diagnose sepsis, which may enlighten innovative approaches to treat this disease [6]
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