Department for BioMedical Research, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland.
Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3008, Bern, Switzerland.
Cell Death Dis. 2021 Apr 6;12(4):366. doi: 10.1038/s41419-021-03654-3.
The toll-like receptor 5 (TLR5) agonist, CBLB502/Entolimod, is a peptide derived from bacterial flagellin and has been shown to protect against radiation-induced tissue damage in animal models. Here we investigated the protective mechanism of CBLB502 in the liver using models of ischemia-reperfusion injury and concanavalin A (ConA) induced immuno-hepatitis. We report that pretreatment of mice with CBLB502 provoked a concomitant activation of NF-κB and STAT3 signaling in the liver and reduced hepatic damage in both models. To understand the underlying mechanism, we screened for cytokines in the serum of CBLB502 treated animals and detected high levels of IL-22. There was no transcriptional upregulation of IL-22 in the liver, rather it was found in extrahepatic tissues, mainly the colon, mesenteric lymph nodes (MLN), and spleen. RNA-seq analysis on isolated hepatocytes demonstrated that the concomitant activation of NF-κB signaling by CBLB502 and STAT3 signaling by IL-22 produced a synergistic cytoprotective transcriptional signature. In IL-22 knockout mice, the loss of IL-22 resulted in a decrease of hepatic STAT3 activation, a reduction in the cytoprotective signature, and a loss of hepatoprotection following ischemia-reperfusion-induced liver injury. Taken together, these findings suggest that CBLB502 protects the liver by increasing hepatocyte resistance to acute liver injury through the cooperation of TLR5-NF-κB and IL-22-STAT3 signaling pathways.
Toll 样受体 5（TLR5）激动剂 CBLB502/Entolimod 是一种源自细菌鞭毛蛋白的肽，已被证明可在动物模型中保护免受辐射引起的组织损伤。在这里，我们使用缺血再灌注损伤和伴刀豆球蛋白 A（ConA）诱导的免疫性肝炎模型研究了 CBLB502 在肝脏中的保护机制。我们报告说，CBLB502 预处理可同时激活肝脏中的 NF-κB 和 STAT3 信号通路，并减轻两种模型中的肝损伤。为了了解潜在的机制，我们筛选了 CBLB502 处理动物的血清中的细胞因子，并检测到高水平的 IL-22。在肝脏中没有发现 IL-22 的转录上调，而是在肝外组织中发现，主要是结肠、肠系膜淋巴结（MLN）和脾脏。对分离的肝细胞进行 RNA-seq 分析表明，CBLB502 同时激活 NF-κB 信号通路和 IL-22 激活 STAT3 信号通路产生协同的细胞保护转录特征。在 IL-22 敲除小鼠中，IL-22 的缺失导致肝 STAT3 激活减少、细胞保护特征减少以及缺血再灌注诱导的肝损伤后肝保护作用丧失。总之，这些发现表明，CBLB502 通过 TLR5-NF-κB 和 IL-22-STAT3 信号通路的合作增加肝细胞对急性肝损伤的抵抗力来保护肝脏。
