Intestinal IL-17R Signaling Constrains IL-18-Driven Liver Inflammation by the Regulation of Microbiome-Derived Products
Intestinal IL-17R Signaling Constrains IL-18-Driven Liver Inflammation by the Regulation of Microbiome-Derived Products
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DOI：
10.1016/j.celrep.2019.10.042
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发表时间：
2019-11-19
期刊：
影响因子：
8.8
通讯作者：
Kolls, Jay K.
中科院分区：
文献类型：
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作者：
Castillo-dela Cruz, Patricia;Wanek, Alanna G.;Kolls, Jay K.
白细胞介素 (IL)-17 向肠上皮发出信号，调节肠道微生物群。鉴于已报道的肠道菌群失调、细菌易位和肝脏疾病之间的联系，我们假设肠道 IL-17R 信号在减轻肝脏炎症中发挥着关键作用。为了测试这一点，我们在免疫驱动的肝炎模型中研究了肠上皮特异性 IL-17RA 缺陷小鼠。在初始状态下，这些小鼠表现出微生物群失调和细菌产物（CpG DNA）易位增加，从而驱动肝脏 IL-18 的产生。疾病诱导后，肠道 IL-17RA 信号传导的缺失会加剧肝炎和肝细胞死亡。 IL-18 对于疾病恶化是必需的，并且与基于 Ifng 和 Fasl 表达的活化肝淋巴细胞增加相关。因此，肠道 IL-17R 调节 TLR9 配体的易位并限制对肝炎的易感性。这些数据将肠道 Th17 信号传导与肝炎中的微生物组联系起来，对肠道免疫受损的影响以及随后在其他肠外病理中观察到的微生物产物的释放具有更广泛的影响。
Interleukin (IL)-17 signaling to the intestinal epithelium regulates the intestinal microbiome. Given the reported links between intestinal dysbiosis, bacterial translocation, and liver disease, we hypothesize that intestinal IL-17R signaling plays a critical role in mitigating hepatic inflammation. To test this, we study intestinal epithelium-specific IL-17RA-deficient mice in an immune-driven hepatitis model. At the naive state, these mice exhibit microbiome dysbiosis and increased translocation of bacterial products (CpG DNA), which drives liver IL-18 production. Upon disease induction, absence of enteric IL-17RA signaling exacerbates hepatitis and hepatocyte cell death. IL-18 is necessary for disease exacerbation and is associated with increased activated hepatic lymphocytes based on Ifng and Fasl expression. Thus, intestinal IL-17R regulates translocation of TLR9 ligands and constrains susceptibility to hepatitis. These data connect enteric Th17 signaling and the microbiome in hepatitis, with broader implications on the effects of impaired intestinal immunity and subsequent release of microbial products observed in other extra-intestinal pathologies.