ABSTRACT
BACKGROUND: An increasing body of evidence now shows that the long-term mortality of patients with sepsis are associated with various sepsis-related immune cell defects. Alternative splicing (AS), as a sepsis-related immune cell defect, is considered as a potential immunomodulatory therapy target to improve patient outcomes. However, our understanding of the role AS plays in sepsis is currently insufficient. AIM: This study investigated possible associations between AS and the gene regulatory networks affecting immune cells. We also investigated apoptosis and AS functionality in sepsis pathophysiology. METHODS: In this study, we assessed publicly available mRNA-seq data that was obtained from the NCBI GEO dataset (GSE154918), which included a healthy group (HLTY), a mild infection group (INF1), asepsis group (Seps), and a septic shock group (Shock). A total of 79 samples (excluding significant outliers) were identified by a poly-A capture method to generate RNA-seq data. The variable splicing events and highly correlated RNA binding protein (RBP) genes in each group were then systematically analyzed. RESULTS: For the first time, we used systematic RNA-seq analysis of sepsis-related AS and identified 1505 variable AS events that differed significantly (p <= 0.01) across the four groups. In the sepsis group, the genes related to significant AS events, such as, SHISA5 and IFI27, were mostly enriched in the cell apoptosis pathway. Furthermore, we identified differential splicing patterns within each of the four groups. Significant differences in the expression of RNA Binding Protein(RBP) genes were observed between the control group and the sepsis group. RBP gene expression was highly correlated with variant splicing events in sepsis, as determined by co-expression analysis; The expression of DDX24, CBFA2T2, NOP, ILF3, DNMT1, FTO, PPRC1, NOLC1 RBPs were significant reduced in sepsis compared to the healthy group. Finally, we constructed an RBP-AS functional network. CONCLUSION: Analysis indicated that the RBP-AS functional network serves as a critical post-transcriptional mechanism that regulates the development of sepsis. AS dysregulation is associated with alterations in the regulatory gene expression network that is involved in sepsis. Therefore, the RBP-AS expression network could be useful in refining biomarker predictions in the development of new therapeutic targets for the pathogenesis of sepsis.
ABSTRACT
Sepsis 3.0 is defined as a life-threatening organ dysfunction caused by the host' uncontrol response to infection, with poor prognosis, high morbidity and fatality. Sepsis is one of the main causes of death in severe patients. As lack of comprehensive recognition of its pathogenesis, there were not specific treatment on it. It is reported that the T-cell immunoglobulin and mucin-domain-containing molecule (Tim) of Tim-1 play critical role in sepsis inflammation, immune tolerance and apoptosis, which is relative specific factor in assessment of sepsis prognostic and treatment efficiency, indicating that it could be a novel target in sepsis as well as provide a novel direction. This article mainly stated the discovery, structure, distribution and immune effect of Tim-1 as well as the possible role of TIM-1in immunosuppression, lymphocyte proliferation and apoptosis, in order to provide reference for further research the treatment of sepsis.
ABSTRACT
Sepsis-induced acute lung injury (ALI) characterized by devastating hyperinflammatory response in the lungs is the ultimate cause of high mortality and mobility in septic patients. miR-155 was reported to be significantly upregulated in sepsis-induced ALI cases and alleviated inflammation in septic lung injury in mouse and cell models. However, the detailed role of miR-155 and its underlying mechanism in sepsis-associated ALI remain to be further explored. In vivo, a cecal ligation and puncture (CLP)-induced ALI mouse model was successfully established. miR-155 expression was significantly higher in CLP mice compared with control mice. miR-155 inhibitor attenuated histopathological changes, lung apoptosis, lung inflammation, and increased the survival rate in CLP-induced ALI mice. In vitro, miR-155 expression increased in murine alveolar epithelial cells MLE-12 stimulated with lipopolysaccharide (LPS) and downregulation of miR-155 suppressed apoptosis and the release of inflammatory cytokines in LPS-stimulated MLE-12 cells. In addition, luciferase reporter assay and RNA immunoprecipitation (RIP) demonstrated that SIRT1 was a direct target of miR-155 in LPS-treated MLE-12 cells. Moreover, miR-155 partially reversed the inhibitory effects of SIRT1 on apoptosis and inflammatory response in LPS-stimulated MLE-12 cells. In summary, these results demonstrated that downregulation of miR-155 attenuated sepsis-induced ALI in vivo and in vitro by targeting SIRT1.