Enteral virus depletion modulates experimental acute pancreatitis via toll-like receptor 9 signaling
Enteral virus depletion modulates experimental acute pancreatitis via toll-like receptor 9 signaling
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肠道病毒耗竭通过 Toll 样受体 9 信号传导调节实验性急性胰腺炎。
DOI：
10.1016/j.bcp.2019.113710
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发表时间：
2020-01-01
影响因子：
5.8
通讯作者：
Sun, Jia
中科院分区：
文献类型：
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作者：
Li, Jiahong;Pan, Xiaohua;Sun, Jia
栖息在肠道中的肠道病毒对肠道的先天性和适应性免疫以及由此产生的远距离器官具有深远的影响。急性胰腺炎（acute pancreatitis，AP）是一种常见的腹部炎症性疾病，肠道细菌在其中起着不可或缺的作用，尤其是重症时，可引起局部和全身并发症。到目前为止，人们对肠道病毒在AP病理生理学中的作用知之甚少。在这项研究中，我们评估了肠道病毒清除口服抗病毒鸡尾酒（AVC）对雨蛙素（Cae）过度刺激诱导的实验性AP的影响及其机制。我们发现AVC治疗减轻了实验性AP，伴随着胰腺和肠中固有免疫细胞浸润和TLR 9表达和信号传导的抑制。此外，AVC给药减少AP诱导的白细胞介素-6（IL-6）产生、IL-6激活的信号转导和转录激活因子3（STAT 3）信号转导。一致地，AP诱导的STAT 3应答性趋化因子，特别是单核细胞趋化蛋白-1（MCP-1）和趋化因子（C-X-C基序）配体1（CXCL 1）的表达减少，从而有助于调节胰腺免疫环境。用Toll样受体9（TLR 9）激动剂处理小鼠通过激活IL 6/STAT 3信号传导和下游趋化因子产生而消除了AVC的保护作用。相反，用TLR 9拮抗剂模拟AVC治疗小鼠，对AP产生保护作用。总的来说，这些结果表明肠道病毒的消耗通过抑制TLR 9信号传导保护小鼠免受实验性AP。因此，我们的研究暗示了肠道病毒在AP中以前未被认识的作用。
Enteric viruses that inhabit the intestine have profound effects on innate and adaptive immunity of the gut and thus distant organs. Acute pancreatitis (AP) is a common abdominal inflammatory disease, in which gut bacteria play an indispensable part, particularly in the severe form with local and systemic complications. So far, little is known about the role of enteric viruses in the pathophysiology of AP. In this study, we evaluated the effect of enteric virus depletion by oral anti-viral cocktail (AVC) on caerulein (Cae)-hyperstimulation induced experimental AP and underlying mechanisms. We found that AVC treatment alleviated experimental AP, accompanied by suppressed innate immune cell infiltration and TLR9 expression and signaling in pancreas and intestine. Furthermore, AVC administration reduced AP-induced interleukin-6 (IL-6) production, IL-6-activated signal transducers and activators of transcription 3 (STAT3) signaling. Concordantly, expression of AP-induced STAT3-responsive chemokines, especially monocyte chemotactic protein-1 (MCP-1) and chemokine (C-X-C motif) ligand 1 (CXCL1) was reduced, thereby contributing to modulated pancreatic immune milieu. Treatment of mice with a toll-like receptor 9 (TLR9) agonist abolished the protective effect of AVC by activation of IL6/STAT3 signaling and downstream chemokine production. Conversely, treatment of mice with TLR9 antagonists, mimicking AVC, exerted protective effects against AP. Collectively, these results suggest that depletion of enteric viruses protects mice from experimental AP through inhibiting TLR9 signaling. Our study therefore implies a previously unrecognized role of enteric viruses in AP.