Introduction
Acute pancreatitis (AP) is a common acute inflammatory disease of the abdomen. ATP citrate lyase (ACLY) has been shown to play a critical role in mitigating acute pancreatitis-associated injury. Lentinan, a multifunctional polysaccharide derived from shiitake mushrooms, exhibits biological activities such as anti-inflammatory, antioxidant, and immunomodulatory effects, and is widely used in clinical settings. However, the role of Lentinan in acute pancreatitis remains unclear.
Aims & Methods
This study aimed to investigate the protective effects of Lentinan against acute pancreatitis and whether this protection depends on ATP citrate lyase. Adult healthy male C57BL/6 mice were randomly divided into control group, acute pancreatitis group, and Lentinan + acute pancreatitis group. The cerulein-LPS induced AP model was established by intraperitoneal injection of cerulein solution (100 μg/kg body weight) 10 times at hourly intervals, followed by a single injection of lipopolysaccharide (5 mg/kg) immediately after the last cerulein injection. In the lentinan + acute pancreatitis group, mice were pretreated with intraperitoneal injections of of Lentinan solution (50 mg/kg, 100 mg/kg, or 200 mg/kg) for three consecutive days before AP induction. The severity of pancreatitis was assessed by comparing plasma activities of amylase, lipase, alanine aminotransferase, aspartate aminotransferase, and plasma levels of urea, and creatinine, as well as pancreatic histopathological scores. Systemic inflammatory response was evaluated by measuring plasma IL-1β and TNF-α levels through enzyme-linked immunosorbent assay. Pancreatic infiltration of macrophages and neutrophils was detected by immunofluorescence, and protein levels of ACLY, NLRP3, and IL-1β in pancreatic tissues were measured by Western blot. To further validate the critical role of ACLY, AP was induced in mice with pancreas-specific ACLY knockout, with Lentinan pretreatment.
Results
Lentinan significantly alleviated pancreatic histopathological damage caused by AP, including edema, necrosis, and inflammatory cell infiltration. It also reduced plasma aminotransferase activity, creatinine, and urea levels, but did not significantly decrease plasma amylase or lipase activity. A higher dose of Lentinan (200 mg/kg) was less effective than lower doses in reducing plasma aminotransferase, creatinine, and urea in AP mice, possibly due to greater hepatorenal toxicity. Therefore, a moderate dose of Lentinan (100 mg/kg) provided effective protection against acute pancreatitis and was therefore selected for subsequent experiments. Additionally, Lentinan reduced pancreatic infiltration of macrophages and neutrophils, decreased plasma pro-inflammatory cytokine levels, upregulated pancreatic ACLY protein expression, and downregulated the levels of NLRP3 inflammasome and IL-1β proteins in pancreatic tissues. In mice with pancreas-specific ACLY knockout, both local pancreatic injury and systemic inflammation caused by AP were significantly exacerbated, and the protective effect of Lentinan against acute pancreatitis was diminished.
Conclusion
Lentinan exerts protective effects against acute pancreatitis by improving local and systemic inflammatory responses. The expression of pancreatic ACLY is indispensable for mediating this protective effect, which was partially achieved through the inhibition of the NLRP3 inflammasome pathway. The present study establishes a novel mechanism for this clinically available immunomodulator, which could have potential therapeutic implications in acute pancreatitis.