Adenosine A2a receptor stimulation blocks development of nonalcoholic steatohepatitis in mice by multilevel inhibition of signals that cause immunolipotoxicity
Adenosine A2a receptor stimulation blocks development of nonalcoholic steatohepatitis in mice by multilevel inhibition of signals that cause immunolipotoxicity
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DOI：
10.1016/j.trsl.2016.11.009
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发表时间：
2017-04-01
影响因子：
7.8
通讯作者：
Carini, Rita
中科院分区：
文献类型：
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作者：
Alchera, Elisa;Rolla, Simona;Carini, Rita
脂肪毒性和免疫炎症与脂肪变性向非酒精性脂肪性肝炎（NASH）的演变有关。本研究报告了腺苷A2 a受体（A2 aR）激活通过调节CD 4（+）T辅助细胞（Th）的反应来抑制NASH发展的能力，以避免免疫介导的脂毒性增强。在喂食蛋氨酸胆碱缺乏（MCD）饲料的脂肪变性C57 BL/6小鼠和暴露于棕榈酸（PA）的小鼠肝细胞中，分析了A2 aR激动剂CGS 21680对免疫炎症信号、CD 4（+）Th细胞浸润和免疫脂质毒性的影响。CGS 21680抑制脂肪变性小鼠中NASH的发展，并减少参与Th细胞募集或极化的细胞因子和趋化因子（即CXCL 10、CCL 2、肿瘤坏死因子α（TNF α）、肿瘤生长因子（TGF β）和IL-12）。CGS 21680还减少了Th 17、Th 22和Th 1细胞的扩增，并增加了调节性T细胞的免疫抑制活性。在PA处理的小鼠肝细胞中，CGS 21680抑制CXCL 10、TNF α、TGF β、IL-12和CCL 2的产生; CGS 21680还通过Akt/PI 3-激酶刺激和PI 3-激酶负调节因子的抑制来预防JNK依赖性脂毒性及其由IL-17或IL-17加IL-22引起的强化，（从10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN），其被IL-17上调。在MCD肝脏中，CGS 21680降低JNK活化和PTEN表达，并增加Akt磷酸化。总之，A2 aR刺激通过减少Th 17细胞扩增和抑制IL-17诱导的JNK依赖性脂毒性的加重来抑制NASH的发展。这些数据促进了进一步研究的实施，以评估A2 aR激动剂的潜在临床应用，通过能够作为细胞保护剂和免疫调节剂，可以有效地拮抗NASH的多方面发病机制。
Lipotoxicity and immunoinflammation are associated with the evolution of steatosis toward nonalcoholic steatohepatitis (NASH). This study reports the ability of adenosine A2a receptor (A2aR) activation to inhibit NASH development by modulating the responses of CD4(+) T-helper (Th) cells to avoid an immuno-mediated potentiation of lipotoxicity. The effect of the A2aR agonist CGS21680 on immunoin-flammatory signals, CD4(+)Th cell infiltration and immunolipotoxicity was analyzed in steatotic C57BL/6 mice fed with a methionine-choline-deficient (MCD) diet and in mouse hepatocytes exposed to palmitic acid (PA). CGS21680 inhibited NASH development in steatotic mice and decreased cytokines and chemokines involved in Th cell recruitment or polarization (namely CXCL10, CCL2, tumor necrosis factor alfa (TNF alpha, tumor growth factor (TGF beta), and IL-12). CGS21680 also reduced the expansion of Th17, Th22, and Th1 cells and increased the immunosuppressive activity of T regulatory cells. In PA-treated mice hepatocytes, CGS21680 inhibited the production of CXCL10, TNF alpha, TGF beta, IL-12, and CCL2; CGS21680 also prevented JNK-dependent lipotoxicity and its intensification by IL-17 or IL-17 plus IL-22 through Akt/PI3-kinase stimulation and inhibition of the negative regulator of PI3-kinase, (phosphatase and tensin homologue deleted from chromosome 10 (PTEN), which is upregulated by IL-17. In MCD livers, CGS21680 reduced JNK activation and PTEN expression and increased Akt phosphorylation. In conclusion, A2aR stimulation inhibited NASH development by reducing Th17 cell expansion and inhibiting the exacerbation of the IL-17-induced JNK-dependent lipotoxicity. These data promote the implementation of further studies to evaluate the potential clinical application of A2aR agonists that, by being able to function as both cytoprotective and immunomodulat ory agents, could efficiently antagonize the multi-faced pathogenesis of NASH.