Exosomes from patients with septic shock convey miRNAs related to inflammation and cell cycle regulation: new signaling pathways in sepsis?

Abstract

BackgroundExosomes isolated from plasma of patients with sepsis may induce vascular apoptosis and myocardial dysfunction by mechanisms related to inflammation and oxidative stress. Despite previous studies demonstrating that these vesicles contain genetic material related to cellular communication, their molecular cargo during sepsis is relatively unknown. In this study, we evaluated the presence of microRNAs (miRNAs) and messenger RNAs (mRNAs) related to inflammatory response and redox metabolism in exosomes of patients with septic shock.MethodsBlood samples were collected from 24 patients with septic shock at ICU admission and after 7 days of treatment. Twelve healthy volunteers were used as control subjects. Exosomes were isolated by ultracentrifugation, and their miRNA and mRNA content was evaluated by qRT-PCR array.ResultsAs compared with healthy volunteers, exosomes from patients with sepsis had significant changes in 65 exosomal miRNAs. Twenty-eight miRNAs were differentially expressed, both at enrollment and after 7 days, with similar kinetics (18 miRNAs upregulated and 10 downregulated). At enrollment, 35 differentially expressed miRNAs clustered patients with sepsis according to survival. The pathways enriched by the miRNAs of patients with sepsis compared with control subjects were related mostly to inflammatory response. The comparison of miRNAs from patients with sepsis according to hospital survival demonstrated pathways related mostly to cell cycle regulation. At enrollment, sepsis was associated with significant increases in the expression of mRNAs related to redox metabolism (myeloperoxidase, 64-fold; PRDX3, 2.6-fold; SOD2, 2.2-fold) and redox-responsive genes (FOXM1, 21-fold; SELS, 16-fold; GLRX2, 3.4-fold). The expression of myeloperoxidase mRNA remained elevated after 7 days (65-fold).ConclusionsExosomes from patients with septic shock convey miRNAs and mRNAs related to pathogenic pathways, including inflammatory response, oxidative stress, and cell cycle regulation. Exosomes may represent a novel mechanism for intercellular communication during sepsis.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2003-3) contains supplementary material, which is available to authorized users.

MiR-21-3p Plays a Crucial Role in Metabolism Alteration of Renal Tubular Epithelial Cells during Sepsis Associated Acute Kidney Injury via AKT/CDK2-FOXO1 Pathway

“…MicroRNA is known to be one kind of noncoding RNAs that can regulate specific genes expression posttranscriptionally by targeting their mRNAs. Recent studies have revealed that numerous microRNAs involved in the process of sepsis and associated immune suppression, organ malfunction, and metabolism dysregulation [18][19][20][21][22]. These microRNAs serve as either extracellular or intracellular effector molecules targeting special mRNAs to manipulate metabolism and function of cells.…”

Current Status of Septic Cardiomyopathy: Basic Science and Clinical Progress

“…The roles of exosomes in SCM is mainly considered from two mechanisms that are exosomal nicotinamide adenine dinucleotide phosphate (NADPH) and microRNA-223 (Monteiro et al, 2017). A study has shown that exosomes can induce vascular apoptosis and myocardial dysfunction by the mechanisms that are related to inflammation and oxidative stress (Real et al, 2018). In patients with sepsis, increased platelet-derived exosomes containing NADPH oxidase subunits similar to phagocytes in blood can help to produce ROS.…”

Roles and Functions of Exosomal Non-coding RNAs in Vascular Aging

“…As the proinflammatory regulator in ECs, miR-92a could activate inflammatory cytokines and chemokines and promote monocyte adhesion [30] while miR-21 could induce the expression of C-C motif chemokine 2 (CCL2) and vascular cell adhesion protein 1 (VCAM-1) by enhancing the activity of the transcription factor AP-1 [31]. It had been demonstrated that some miRNAs from exosomes (miR-15a, miR-27a and miR-34a) were increased in patients with sepsis, which could modulate the inflammatory response [32,33]. Oppositively, Li et al discovered that exosomes containing miR-223 inhibited intercellular adhesion molecule-1 (ICAM-1) expression during inflammation through regulating the NF-κB and MAPK pathways [34].…”