CircHIPK3 Promotes Pyroptosis in Acinar Cells Through Regulation of the miR 193a 5p/GSDMD Axis
Acute pancreatitis (AP) especially severe acute pancreatitis (SAP) is an extremely dangerous illness with a high mortality rate. Pyroptotic cells release their cellular contents and inflammatory factors, aggravating the inflammatory response. Pyroptosis may be the main mode of acinar cell death during AP. The circular RNA circHIPK3 is expressed in pancreatic tissue and is associated with inflammatory response. In this study, we focused on the role and underlying mechanism of circHIPK3 in AP. We found that the expression of circHIPK3 was significantly elevated in serum of patients with AP and in caerulein stimulated AR42J cells and was associated with caspase 1 and caspase 11 activation. circHIPK3 silencing ameliorated caerulein induced cell damage and reduced the release of inflammatory factors IL 1b, IL 6, IL 8, and TNF a and inhibited the activation of caspase 1 and caspase 11. In addition, circHIPK3 bound to miR 193a 5p and negatively regulated its expression. Inhibition of miR 193a 5p increased the release of IL 1b, IL 6, IL 8, and TNF a and activated caspase 1 and caspase 11, thereby counteracting the effect of circHIPK3 silencing on caerulein induced cell damage. Furthermore, we identified GSDMD as a target gene of miR 193a 5p, which is the key gene for pyroptosis. Interfering with the expression of GSDMD can increase cell viability, reduce the secretion of inflammatory cytokines, and suppress the activation of cleaved caspase 1 and caspase 11. Silencing GSDMD reversed the effects of miR 193a 5p inhibitors on caerulein induced damage. In conclusion, circHIPK3 promotes pyroptosis in acinar cells through regulation of the miR 193a 5p/GSDMD axis, which eventually aggravates AP disease.
Frontiers in Medicine