Deletion of tumour necrosis factor α receptor 1 elicits an increased TH17 immune response in the chronically inflamed liver
Deletion of tumour necrosis factor α receptor 1 elicits an increased TH17 immune response in the chronically inflamed liver
复制标题
DOI：
10.1038/s41598-019-40324-z
复制
发表时间：
2019-03-12
影响因子：
4.6
通讯作者：
Tiegs, Gisa
中科院分区：
文献类型：
--
作者：
Berkhout, Laura;Barikbin, Roja;Tiegs, Gisa
已知肿瘤坏死因子a受体1（TNFR 1）活化诱导细胞死亡、炎症和纤维化，但也诱导肝细胞存活和再生。多药耐药蛋白2基因敲除（Mdr 2（-/））小鼠是慢性肝炎和炎症相关肝细胞癌（HCC）发展的模型。这项研究分析了TNFR 1介导的信号传导的缺乏如何影响细胞因子和趋化因子的产生，免疫细胞的募集，并最终影响Mdr 2（-/-）小鼠模型中的肝损伤和纤维化组织重塑。我们发现Tnfr 1（-/-）/Mdr 2（-/-）小鼠的ALT、ALP和胆红素的血浆水平升高，胶原蛋白含量和纤维化标志物显著高于Mdr 2（-/-）小鼠。Tnfr 1（-/-）/Mdr 2（-/-）小鼠肝脏中炎性细胞因子（IL 1b、IL 23、Tgfb 1、IL 17 a）、趋化因子（Ccl 2、Cxcl 1、Cx 3cl 1）和趋化因子受体（Ccr 6、Cxcr 6、Cx 3cr 1）的表达谱表明TH 17细胞浸润。流式细胞术分析证实，Tnfr 1（-/-）/Mdr 2（-/-）小鼠中加重的组织损伤与肝脏中TH 17细胞募集增加和IL-17产生增加密切相关。此外，我们在Tnfr 1（-/-）/Mdr 2（-/-）小鼠中观察到RIPK 3的肝脏活化增加，这与坏死性细胞死亡无关。相反，在Tnfr 1（-/-）/Mdr 2（-/-）小鼠的肝脏中，浸润的CX 3CR 1（+）单核细胞的频率随着时间的推移而增加，这些小鼠表达的Ripk 3水平显著高于Mdr 2（-/-）小鼠。总之，我们得出结论，TNFR 1介导的信号传导的缺乏并没有改善Mdr 2（-/-）小鼠的病理表型。相反，它导致TH 17细胞和CX 3CR 1（+）单核细胞向损伤组织中的浸润增强，伴随着RIPK 3活化和IL-17产生增加。
Tumour necrosis factor a receptor 1 (TNFR1) activation is known to induce cell death, inflammation, and fibrosis but also hepatocyte survival and regeneration. The multidrug resistance protein 2 knockout (Mdr2(-/)) mice are a model for chronic hepatitis and inflammation-associated hepatocellular carcinoma (HCC) development. This study analysed how the absence of TNFR1 mediated signalling shapes cytokine and chemokine production, immune cell recruitment and ultimately influences liver injury and fibrotic tissue remodelling in the Mdr2(-/-) mouse model. We show that Tnfr1(-/-)/Mdr2(-/-) mice displayed increased plasma levels of ALT, ALP, and bilirubin as well as a significantly higher collagen content, and markers of fibrosis than Mdr2(-/-) mice. The expression profile of inflammatory cytokines (Il1b, Il23, Tgfb1, Il17a), chemokines (Ccl2, Cxcl1, Cx3cl1) and chemokine receptors (Ccr6, Cxcr6, Cx3cr1) in livers of Tnfr1(-/-)/Mdr2(-/-) mice indicated TH17 cell infiltration. Flow cytometric analysis confirmed that the aggravated tissue injury in Tnfr1(-/-)/Mdr2(-/-) mice strongly correlated with increased hepatic recruitment of TH17 cells and enhanced IL-17 production in the injured liver. Moreover, we observed increased hepatic activation of RIPK3 in Tnfr1(-/-)/Mdr2(-/-) mice, which was not related to necroptotic cell death. Rather, frequencies of infiltrating CX3CR1(+) monocytes increased over time in livers of Tnfr1(-/-)/Mdr2(-/-) mice, which expressed significantly higher levels of Ripk3 than those of Mdr2(-/-) mice. Overall, we conclude that the absence of TNFR1-mediated signalling did not improve the pathological phenotype of Mdr2(-/-) mice. It instead caused enhanced infiltration of TH17 cells and CX3CR1(+) monocytes into the injured tissue, which was accompanied by increased RIPK3 activation and IL-17 production.