Circulating exosomal miR‐155‐5p contributes to severe acute pancreatitis‐associated intestinal barrier injury by targeting SOCS1 to activate NLRP3 inflammasome‐mediated pyroptosis

Abstract

AbstractSevere acute pancreatitis (SAP) represents a common and serious disease that can cause intestinal barrier dysfunction. However, the pathogenesis of this barrier dysfunction remains unclear. Exosomes are a new intercellular communication method involved in multiple diseases. Consequently, the present study sought to determine the function of circulating exosomes in barrier dysfunction associated with SAP. A rat model of SAP was established by injecting biliopancreatic duct with 5% sodium taurocholate. Circulating exosomes were purified from SAP (SAP‐Exo) and sham operation rats (SO‐Exo) using a commercial kit. In vitro, SO‐Exo and SAP‐Exo were cocultured with rat intestinal epithelial (IEC‐6) cells. In vivo, naive rats were treated with SO‐Exo and SAP‐Exo. We found SAP‐Exo‐induced pyroptotic cell death and barrier dysfunction in vitro. In addition, miR‐155‐5p exhibited a remarkable increase in SAP‐Exo than SO‐Exo, and miR‐155‐5p inhibitor partially abolished the negative effect of SAP‐Exo on IEC‐6 cells. Furthermore, miRNA functional experiments revealed that miR‐155‐5p could induce pyroptosis and barrier loss in IEC‐6 cells. Overexpression of suppressor of cytokine signaling 1 (SOCS1), a miR‐155‐5p target, could partially reverse IEC‐6 cells from the harmful impact of miR‐155‐5p. In vivo, SAP‐Exo significantly triggered pyroptosis in intestinal epithelial cells and caused intestinal injury. In addition, blocking exosome release with GW4869 attenuated intestinal injury in SAP rats. In summary, our study demonstrated that miR‐155‐5p is highly enriched in circulating exosomes from SAP rat plasma and can be transported to intestinal epithelial cells, where it targets SOCS1 to activate NOD‐like receptor protein 3 (NLRP3) inflammasome‐mediated pyroptosis leading to intestinal barrier damage.