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

Chaohao Huang,Feng Ma,Jian Huang,Mengtao Zhou,Yanghua Qin,Zhonglin Huang,Bicheng Chen,Tan Zhang,Shengchuan Chen,Genhong Cheng,Dapei Li

doi:10.3389/fimmu.2019.00980

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.

Highlights

Acute pancreatitis (AP) is an inflammatory condition of the pancreas, that frequently leads to systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndromes (MODS), and even death without early intervention [1]
The protective effect of polyI:C on pancreatitis was evaluated in the caerulein-AP experimental mouse model at 24 h after the first injection of caerulein (Figure 1A)
Neutrophils were recruited into the injured pancreases during pancreatitis progression, whereas notably fewer MPO+ cells were observed in the injured pancreases from caerulein-AP mice pretreated with polyI:C

Summary

Introduction

Acute pancreatitis (AP) is an inflammatory condition of the pancreas, that frequently leads to systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndromes (MODS), and even death without early intervention [1]. Reactive oxygen species (ROS) generated by injured pancreatic acinar cells and infiltrated immune cells are key factors in the progression of pancreatitis [5]. Previous studies on AP have suggested that damage of pancreatic acinar cells results in the upregulation of inflammatory cytokines and chemokines [6]. They initiate the inflammatory response and the recruitment of inflammatory cells, which leads to pancreatitis [7]. High levels of HO-1 are an indicator of severe tissue damage and oxidative stress, which require a stronger anti-oxidant reaction [10]. HO-1 could be used as an indicator for measuring the severity of damage and inflammation in AP

Methods

Results

Conclusion