Abstract
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-1β, IL-6, IL-8, and TNF-α 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-1β, IL-6, IL-8, and TNF-α 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.
Highlights
The occurrence and development of acute pancreatitis (AP) have been the focus of research in the field of surgery [1]
We focused on the role and underlying mechanism of circHIPK3 in Acute pancreatitis (AP). circHIPK3 is a circular RNA derived from the second exon of the HIPK3 gene. circHIPK3 is highly expressed in liver, brain, and lung [13,14,15] and has shown an important role in the regulation of cell survival, oxidative damage, and inflammation [16,17,18]
The results showed that caerulein significantly reduced cell viability (Figure 1B), enhanced the secretion of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α (Figure 1C), and circHIPK3 in Acute Pancreatitis increased the activity of amylase in a time-dependent manner (Figure 1D) compared with controls
Summary
The occurrence and development of acute pancreatitis (AP) have been the focus of research in the field of surgery [1]. CircHIPK3 in Acute Pancreatitis cellular contents and inflammatory factors, such as tumor necrosis factor alpha (TNF-α) and IL-1β, aggravating the inflammatory response [6]. This mode of acinar cell death has always been a hot spot in AP research. CircHIPK3 is highly expressed in liver, brain, and lung [13,14,15] and has shown an important role in the regulation of cell survival, oxidative damage, and inflammation [16,17,18]. Mechanistic study showed that that circHIPK3 promoted pyroptosis and inflammation through regulation of the miR-193a-5p/GSDMD axis in AR42J cells. CircHIPK3 could become a new biomarker and therapeutic target in AP
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