TLR3 Ligand PolyI:C Prevents Acute Pancreatitis Through the Interferon-β/Interferon-α/β Receptor Signaling Pathway in a Caerulein-Induced Pancreatitis Mouse Model

Abstract

Acute pancreatitis (AP) is a common and devastating inflammatory disorder of the pancreas. However, there are still no effective treatments available for the disease. Therefore, it is important to discover new therapeutic targets and strategies for better treatment and prognosis of AP patients. Toll-like receptor 3 (TLR3) ligand polyI:C is a double-stranded RNA mimic that can be used as an immune stimulant. Our current study indicates that polyI:C exerted excellent anti-inflammatory effects in a caerulein-induced AP mouse model and taurocholate-induced pancreatic acinar cell line injury model. We found that polyI:C triggers type I interferon (IFN) production and downstream IFN-α/β receptor (IFNAR)-dependent signaling, which play key roles in protecting the pancreas from inflammatory injury. Knockout of IFN-β and IFNAR in mice abolished the preventive effects of polyI:C on caerulein-induced AP symptoms, which include pancreatic edema, neutrophil infiltration, the accumulation of reactive oxygen species (ROS), and inflammatory gene expression. Treating pancreatic acinar 266-6 cells with an IFNAR inhibitor, which blocks the interaction between type I IFN and IFNAR, diminishes the downregulation of oxidative stress by polyI:C. Additionally, a subsequent transcriptome analysis on the role of polyI:C in treating pancreatitis suggested that chemotaxis of neutrophils and the production of ROS were inhibited by polyI:C in the pancreases damaged by caerulein injection. Thus, polyI:C may act as a type I IFN inducer to alleviate AP, and it has the potential to be a promising therapeutic agent used at the early stages of AP.

LincRNA‐EPS alleviates severe acute pancreatitis by suppressing HMGB1‐triggered inflammation in pancreatic macrophages

“…The experimental Cer-AP mice were intraperitoneally administered with caerulein (200 µg/kg or 100 µg/kg) 8 or 10 times hourly. 8 The experimental NaTc-SAP mice were induced by pancreatic ductal retrograde infusion of sodium taurocholate (NaTc) as previously described. 22 Briefly, after the mice were anaesthetized with pentobarbital, laparotomy was performed and the duodenum was taken out gently from the depths of the wound in the middle of the abdomen.…”

“…6,7 These inflammatory mediators further amplify the pancreatic inflammation and tissue damage by recruiting neutrophils and activating more macrophages, leading to pancreas oedema, intrapancreatic haemorrhage, acinar necrosis, and upregulation of serum inflammatory cytokines, chemokines, amylase and lipase. 5,8,9 Local pancreatic injuries induce SIRS and inflammation in extra-pancreatic organs including lung, liver and gut, which may develop to AP-MODS. [10][11][12] Hence, a novel strategy targeting the inflammatory responses in the pancreatic macrophage at the initial phase is a promising early intervention for AP and SAP.…”

Necrostatin‑1 protects mice from acute lung injury by suppressing necroptosis and reactive oxygen species

“…However, overproduction of ROS has been implicated in the development of various chronic and degenerative diseases, including cancer, and respiratory, neurodegenerative and digestive diseases (20). ROS are likely to be among the inducers of acute or chronic inflammation that lead to cellular damage, since antioxidants reduce activation of inflammatory pathways (21). The antioxidant defense system can be overwhelmed during sustained severe inflammation, as observed in acute lung inflammation, inflammatory bowel disease, neurodegenerative disorders, cardiovascular diseases and aging (22).…”

Okra pectin relieves inflammatory response and protects damaged intestinal barrier in caerulein‐induced acute pancreatic model

“…1, it was revealed that OP or COP could significantly reduce the inflammation aroused by AP, while the effect of OP was better compared with COP. After the modeling was completed, the mice in the APG group were slow and listless and severe ascites were observed, which suggested that the modeling had succeeded 34 . Compared with APG, the mice in OPG and COPG groups exhibited significantly reduced pancreas edema (Fig.…”