Abstract
Sepsis is a systemic inflammatory disorder induced by a dysregulated immune response to infection resulting in dysfunction of multiple critical organs, including the intestines. Previous studies have reported contrasting results regarding the abilities of exosomes circulating in the blood of sepsis mice and patients to either promote or suppress inflammation. Little is known about how the gut epithelial cell-derived exosomes released in the intestinal luminal space during sepsis affect mucosal inflammation. To study this question, we isolated extracellular vesicles (EVs) from intestinal lavage of septic mice. The EVs expressed typical exosomal (CD63 and CD9) and epithelial (EpCAM) markers, which were further increased by sepsis. Moreover, septic-EV injection into inflamed gut induced a significant reduction in the messaging of pro-inflammatory cytokines TNF-α and IL-17A. MicroRNA (miRNA) profiling and reverse transcription and quantitative polymerase chain reaction (RT-qPCR) revealed a sepsis-induced exosomal increase in multiple miRNAs, which putatively target TNF-α and IL-17A. These results imply that intestinal epithelial cell (IEC)-derived luminal EVs carry miRNAs that mitigate pro-inflammatory responses. Taken together, our study proposes a novel mechanism by which IEC EVs released during sepsis transfer regulatory miRNAs to cells, possibly contributing to the amelioration of gut inflammation.
Highlights
Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host immune response to infection [1]
For the sake of simplicity and clarity, in the sections that follow we focus on the extracellular vesicles (EVs) from the large intestine lavage fluid, we are aware that some of these EVs isolated may have been secreted from the small intestine
Using a TargetScan bioinfomatics analysis that concentrated on miRNAs upregulated in the intestinal epithelial EVs during sepsis, we examined those miRNAs predicted to target TNF-α, and IL-17A
Summary
Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host immune response to infection [1]. Splanchnic hypoperfusion causes gut injury, which in turn results in the release of gut-derived pro-inflammatory factors [4,5] that reach the systemic circulation through the mesenteric lymph [6,7,8,9]; a process thought to exacerbate and maintain an inflammatory response that culminates in multiple organ failure [10]. The gut has been described as the “motor” of multiple organ dysfunction syndrome (MODS) both in sepsis and other critical illnesses, due to its potential role as a portal for generating systemic immune responses [11]. Pro-inflammatory cytokines secreted into the intestinal luminal space during sepsis are thought to act as important regional mediators that complicate the pathology of intestinal failure [14]. As detailed we have explored the role of extracellular vesicles (EVs) as an alternative/additive regional mediator to luminally secreted cytokines in sepsis
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