Hypoxia-Inducible Factor-2α Reprograms Liver Macrophages to Protect Against Acute Liver Injury Through the Production of Interleukin-6
Hypoxia-Inducible Factor-2α Reprograms Liver Macrophages to Protect Against Acute Liver Injury Through the Production of Interleukin-6
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DOI：
10.1002/hep.30954
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发表时间：
2020-02-04
期刊：
影响因子：
13.5
通讯作者：
Ju, Cynthia
中科院分区：
文献类型：
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作者：
Gao, Rachel Y.;Wang, Meng;Ju, Cynthia
背景和目的对乙酰氨基酚（APAP）过量是急性肝衰竭最常见的原因，在美国超过三分之一的患者中导致死亡或肝移植。唯一的解毒剂n -乙酰半胱氨酸的有效性在APAP摄入后迅速下降，早在患者因严重肝损伤症状入院之前。APAP的直接肝毒性引发了一系列先天免疫反应，可能加剧或限制组织损伤的进展。更好地理解这种复杂的机制将有助于发现治疗干预的目标。方法和结果我们观察到APAP刺激导致肝脏和肝巨噬细胞（M phi s）中的缺氧诱导因子（hif）稳定，特别是HIF-2 α。髓细胞中HIF-2 α基因的遗传缺失（HIF-2 α (mye/-)）显著加重了APAP诱导的肝损伤（AILI），但不影响APAP的生物活化和解毒。相比之下，与野生型小鼠相比，HIF-2 α (mye/-)小鼠的肝脏和血清中肝保护细胞因子白细胞介素6 （IL-6）、其下游信号转导器和肝细胞转录因子3的激活水平以及肝脏M phi IL-6的表达在apap攻击后显著降低。体外实验显示，缺氧诱导肝M - phi s产生IL-6，而这种诱导作用在HIF-2 α缺失的肝M - phi s中被消除。通过外源性IL-6恢复IL-6可改善HIF-2 α (mye/-)小鼠的AILI。最后，在肝细胞特异性IL-6受体敲除小鼠中，IL-6介导的对AILI的肝保护作用被消除。结论APAP治疗导致肝M phi s中的HIF-2 α稳定，HIF-2 α随后重新编程肝M phi s产生肝保护细胞因子IL-6，从而改善AILI。
Background and Aims Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure, resulting in death or liver transplantation in more than one third of patients in the United States. The effectiveness of the only antidote, N-acetylcysteine, declines rapidly after APAP ingestion, long before patients are admitted to the clinic with symptoms of severe liver injury. The direct hepatotoxicity of APAP triggers a cascade of innate immune responses that may exacerbate or limit the progression of tissue damage. A better understanding of this complex mechanism will help uncover targets for therapeutic interventions.Approach and Results We observed that APAP challenge caused stabilization of hypoxia-inducible factors (HIFs) in the liver and hepatic macrophages (M phi s), particularly HIF-2 alpha. Genetic deletion of the HIF-2 alpha gene in myeloid cells (HIF-2 alpha(mye/-)) markedly exacerbated APAP-induced liver injury (AILI) without affecting APAP bioactivation and detoxification. In contrast, hepatic and serum levels of the hepatoprotective cytokine interleukin 6 (IL-6), its downstream signal transducer and transcription factor 3 activation in hepatocytes, as well as hepatic M phi IL-6 expression were markedly reduced in HIF-2 alpha(mye/-) mice compared to wild-type mice post-APAP challenge. In vitro experiments revealed that hypoxia induced IL-6 production in hepatic M phi s and that such induction was abolished in HIF-2 alpha-deleted hepatic M phi s. Restoration of IL-6 by administration of exogenous IL-6 ameliorated AILI in HIF-2 alpha(mye/-) mice. Finally, IL-6-mediated hepatoprotection against AILI was abolished in hepatocyte-specific IL-6 receptor knockout mice.Conclusions The data demonstrate that APAP treatment leads to HIF-2 alpha stabilization in hepatic M phi s and that HIF-2 alpha subsequently reprograms hepatic M phi s to produce the hepatoprotective cytokine IL-6, thereby ameliorating AILI.