TLR3 Ligand PolyI:C Prevents Acute Pancreatitis Through the Interferon-β/Interferon-α/β Receptor Signaling Pathway in a Caerulein-Induced Pancreatitis Mouse Model
TLR3 Ligand PolyI:C Prevents Acute Pancreatitis Through the Interferon-β/Interferon-α/β Receptor Signaling Pathway in a Caerulein-Induced Pancreatitis Mouse Model
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TLR3 配体 PolyI:C 在雨蛙素诱导的胰腺炎小鼠模型中通过干扰素-β/干扰素-α/β 受体信号通路预防急性胰腺炎
DOI：
10.3389/fimmu.2019.00980
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发表时间：
2019-05
期刊：
影响因子：
--
通讯作者：
Zhou Mengtao
中科院分区：
文献类型：
--
作者：
Huang Chaohao;Chen Shengchuan;Zhang Tan;Li Dapei;Huang Zhonglin;Huang Jian;Qin Yanghua;Chen Bicheng;Cheng Genhong;Ma Feng;Zhou Mengtao
急性胰腺炎（acute pancreatitis，AP）是一种常见的胰腺炎性疾病.然而，目前仍没有有效的治疗方法。因此，寻找新的治疗靶点和策略对改善AP的治疗和预后具有重要意义。Toll样受体3（TLR 3）配体polyI：C是一种双链RNA模拟物，可用作免疫刺激剂。我们目前的研究表明，polyI：C发挥了良好的抗炎作用，在雨蛙素诱导的AP小鼠模型和牛磺胆酸诱导的胰腺腺泡细胞系损伤模型。我们发现polyI：C触发I型干扰素（IFN）的产生和下游IFN-α/β受体（IFNAR）依赖性信号传导，这在保护胰腺免受炎症损伤方面发挥关键作用。在小鼠中敲除IFN-β和IFNAR消除了polyI：C对雨蛙素诱导的AP症状的预防作用，这些症状包括胰腺水肿、中性粒细胞浸润、活性氧（ROS）积累和炎症基因表达。用阻断I型IFN和IFNAR之间相互作用的IFNAR抑制剂处理胰腺腺泡266-6细胞，减少了polyI：C对氧化应激的下调。此外，随后对polyI：C在治疗胰腺炎中的作用的转录组分析表明，在雨蛙肽注射损伤的胰腺中，polyI：C抑制中性粒细胞的趋化性和ROS的产生。因此，polyI：C可能作为I型IFN诱导剂来缓解AP，并且它有可能成为AP早期阶段的有前途的治疗剂。
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.
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影响因子：
7.3
作者：
J. Peake;Katsuhiko Suzuki
通讯作者：
J. Peake;Katsuhiko Suzuki
影响因子：
29.4
作者：
Kang R;Zhang Q;Hou W;Yan Z;Chen R;Bonaroti J;Bansal P;Billiar TR;Tsung A;Wang Q;Bartlett DL;Whitcomb DC;Chang EB;Zhu X;Wang H;Lu B;Tracey KJ;Cao L;Fan XG;Lotze MT;Zeh HJ 3rd;Tang D
通讯作者：
Tang D
影响因子：
14.9
作者：
Wang X;Spandidos A;Wang H;Seed B
通讯作者：
Seed B
影响因子：
7.6
作者：
Billiau A
通讯作者：
Billiau A
影响因子：
29.4
作者：
Gukovskaya, AS;Vaquero, E;Pandol, SJ
通讯作者：
Pandol, SJ