Rolla Simona, Alchera Elisa, Imarisio Chiara, Bardina Valentina, Valente Guido, Cappello Paola, Mombello Cristina, Follenzi Antonia, Novelli Francesco, Carini Rita
Center for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Città della Salute e della Scienza di Torino, via Cherasco 15, 10126 Turin, Italy Department of Molecular Biotechnology and Health Sciences, via Nizza 56, University of Torino, 10126 Turin, Italy.
Department of Health Sciences, University of Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy.
Clin Sci (Lond). 2016 Feb;130(3):193-203. doi: 10.1042/CS20150405. Epub 2015 Nov 11.
The mechanisms responsible for the evolution of steatosis towards NASH (non-alcoholic steatohepatitis) and fibrosis are not completely defined. In the present study we evaluated the role of CD4(+) T-helper (Th) cells in this process. We analysed the infiltration of different subsets of CD4(+) Th cells in C57BL/6 mice fed on a MCD (methionine choline-deficient) diet, which is a model reproducing all phases of human NASH progression. There was an increase in Th17 cells at the beginning of NASH development and at the NASH-fibrosis transition, whereas levels of Th22 cells peaked between the first and the second expansion of Th17 cells. An increase in the production of IL (interleukin)-6, TNFα (tumour necrosis factor α), TGFβ (transforming growth factor β) and CCL20 (CC chemokine ligand 20) accompanied the changes in Th17/Th22 cells. Livers of IL-17(-/-) mice were protected from NASH development and characterized by an extensive infiltration of Th22 cells. In vitro, IL-17 exacerbated the JNK (c-Jun N-terminal kinase)-dependent mouse hepatocyte lipotoxicity induced by palmitate. IL-22 prevented lipotoxicity through PI3K (phosphoinositide 3-kinase)-mediated inhibition of JNK, but did not play a protective role in the presence of IL-17, which up-regulated the PI3K/Akt inhibitor PTEN (phosphatase and tensin homologue deleted on chromosome 10). Consistently, livers of IL-17(-/-) mice fed on the MCD diet displayed decreased activation of JNK, reduced expression of PTEN and increased phosphorylation of Akt compared with livers of wild-type mice. Hepatic infiltration of Th17 cells is critical for NASH initiation and development of fibrosis in mice, and reflects an infiltration of Th22 cells. Th22 cells are protective in NASH, but only in the absence of IL-17. These data strongly support the potentiality of clinical applications of IL-17 inhibitors that can prevent NASH by both abolishing the lipotoxic action of IL-17 and allowing IL-22-mediated protection.
导致脂肪变性向非酒精性脂肪性肝炎（NASH）和肝纤维化演变的机制尚未完全明确。在本研究中，我们评估了CD4(+)辅助性T（Th）细胞在这一过程中的作用。我们分析了喂食蛋氨酸胆碱缺乏（MCD）饮食的C57BL/6小鼠中不同CD4(+) Th细胞亚群的浸润情况，MCD饮食是一种可重现人类NASH进展各阶段的模型。在NASH发展初期和NASH-肝纤维化转变期，Th17细胞数量增加，而Th22细胞水平在Th17细胞的第一次和第二次扩增之间达到峰值。Th17/Th22细胞变化的同时，白细胞介素（IL）-6、肿瘤坏死因子α（TNFα）、转化生长因子β（TGFβ）和CC趋化因子配体20（CCL20）的产生也增加。IL-17基因敲除小鼠的肝脏可免受NASH发展的影响，其特征是Th22细胞广泛浸润。在体外，IL-17加剧了棕榈酸诱导的依赖c-Jun氨基末端激酶（JNK）的小鼠肝细胞脂肪毒性。IL-22通过磷脂酰肌醇3激酶（PI3K）介导的JNK抑制作用预防脂肪毒性，但在存在IL-17的情况下不发挥保护作用，因为IL-17会上调PI3K/Akt抑制剂第10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）。同样，与野生型小鼠的肝脏相比，喂食MCD饮食的IL-17基因敲除小鼠的肝脏中JNK活化降低，PTEN表达减少，Akt磷酸化增加。Th17细胞的肝脏浸润对于小鼠NASH的起始和肝纤维化发展至关重要，并反映了Th22细胞的浸润情况。Th22细胞在NASH中具有保护作用，但仅在不存在IL-17的情况下。这些数据有力地支持了IL-17抑制剂临床应用的潜力，其可通过消除IL-17的脂肪毒性作用和允许IL-22介导的保护作用来预防NASH。
