Human Antigen R (HuR): A Regulator of Heme Oxygenase-1 Cytoprotection in Mouse and Human Liver Transplant Injury.
Human Antigen R (HuR): A Regulator of Heme Oxygenase-1 Cytoprotection in Mouse and Human Liver Transplant Injury.
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DOI：
10.1002/hep.31093
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Kupiec-Weglinski JW
中科院分区：
文献类型：
--
作者：
Dery KJ;Nakamura K;Kadono K;Hirao H;Kageyama S;Ito T;Kojima H;Kaldas FM;Busuttil RW;Kupiec-Weglinski JW
缺血再灌注损伤（IRI）是肝移植（LT）的一个危险因素。我们已经证明，血红素氧合酶-1（HO-1）的过度表达减轻了LT受者的肝脏IRI。在此，我们假设人抗原R（HuR），即富含腺苷酸-尿苷酸（Au）的mRNA的稳定剂，是LT中肝保护所必需的。在实验组中，HuR/HO-1蛋白表达与肝脏IRI表型相关。在肝温IRI的体外炎症模拟模型中，在原代肝细胞培养物中检测到HuR/HO-1的诱导和细胞因子预处理后的细胞质定位，而HuR沉默导致HO-1的负调节，随后是增强的细胞毒性。使用HuR-抑制剂，我们发现HuR可能通过其3′非翻译区调节HO-1，并导致中性粒细胞活化（CD 69 +/淋巴细胞抗原6复合物基因座G [Ly 6-G]）。骨髓源性巨噬细胞中的HuR沉默降低了HO-1表达，导致促炎细胞因子/趋化因子的诱导。在体外温IRI下HuR沉默转录物的RNA测序揭示了基因胸腺细胞抗原1（THY 1）、乌头酸脱羧酶1（ACOD 1）和前列腺素E合酶（PTGES）的调节。HuR，而不是缺氧诱导蛋白α，在温暖而不是寒冷的缺氧/复氧条件下正调控HO-1。HuR调节再灌注下原代肝细胞、中性粒细胞和巨噬细胞中的HO-1。在HO-1调节下，HuR的辅助抑制减少了微管相关蛋白1A/1B轻链3B（LC 3B），这是自噬体的标志物，表明肝IR中的细胞保护机制。在临床研究中，在再灌注后2小时分析了51例LT患者的肝活检。移植物HuR表达与巨噬细胞（CD 80/CD 86）和中性粒细胞（组织蛋白酶G）标志物呈负相关。肝脏IRI增加HuR/HO‐1表达和炎症基因。高HuR表达的肝移植物显示较低的血清丙氨酸转氨酶/血清天冬氨酸转氨酶水平和改善LT存活。这项翻译研究将HuR鉴定为无菌性肝脏炎症中HO-1介导的细胞保护的调节剂和LT中缺血应激抗性的生物标志物。
Ischemia–reperfusion injury (IRI) represents a risk factor in liver transplantation (LT). We have shown that overexpression of heme oxygenase‐1 (HO‐1) mitigates hepatic IRI in LT recipients. Here, we hypothesized that human antigen R (HuR), the stabilizer of adenylate‐uridylate (AU)‐rich mRNAs, is required for hepatoprotection in LT. In an experimental arm, HuR/HO‐1 protein expression was correlated with hepatic IRI phenotype. In an in vitro inflammation mimic model of hepatic warm IRI, induction of HuR/HO‐1 and cytoplasmic localization following cytokine preconditioning were detected in primary hepatocyte cultures, whereas HuR silencing caused negative regulation of HO‐1, followed by enhanced cytotoxicity. Using the HuR‐inhibitor, we showed that HuR likely regulates HO‐1 through its 3′ untranslated region and causes neutrophil activation (CD69+/lymphocyte antigen 6 complex locus G [Ly6‐G]). HuR silencing in bone marrow–derived macrophages decreased HO‐1 expression, leading to the induction of proinflammatory cytokines/chemokines. RNA sequencing of HuR silenced transcripts under in vitro warm IRI revealed regulation of genes thymus cell antigen 1 (THY1), aconitate decarboxylase 1 (ACOD1), and Prostaglandin E Synthase (PTGES). HuR, but not hypoxia‐inducible protein alpha, positively regulated HO‐1 in warm, but not cold, hypoxia/reoxygenation conditions. HuR modulated HO‐1 in primary hepatocytes, neutrophils, and macrophages under reperfusion. Adjunctive inhibition of HuR diminished microtubule‐associated proteins 1A/1B light chain 3B (LC3B), a marker for autophagosome, under HO‐1 regulation, suggesting a cytoprotective mechanism in hepatic IR. In a clinical arm, hepatic biopsies from 51 patients with LT were analyzed at 2 hours after reperfusion. Graft HuR expression was negatively correlated with macrophage (CD80/CD86) and neutrophil (Cathepsin G) markers. Hepatic IRI increased HuR/HO‐1 expression and inflammatory genes. High HuR–expressing liver grafts showed lower serum alanine aminotransferase/serum aspartate aminotransferase levels and improved LT survival. This translational study identifies HuR as a regulator of HO‐1–mediated cytoprotection in sterile liver inflammation and a biomarker of ischemic stress resistance in LT.
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影响因子：
25.7
作者：
Nakamura K;Zhang M;Kageyama S;Ke B;Fujii T;Sosa RA;Reed EF;Datta N;Zarrinpar A;Busuttil RW;Araujo JA;Kupiec-Weglinski JW
通讯作者：
Kupiec-Weglinski JW
影响因子：
5.8
作者：
Li YJ;Wang CH;Zhou Y;Liao ZY;Zhu SF;Hu Y;Chen C;Luo JM;Wen ZK;Xu L
通讯作者：
Xu L
影响因子：
4.8
作者：
Lee, PJ;Jiang, BH;Choi, AMK
通讯作者：
Choi, AMK
影响因子：
5.3
作者：
Galban, Stefanie;Kuwano, Yuki;Gorospe, Myriam
通讯作者：
Gorospe, Myriam
影响因子：
4.3
作者：
Gubin, Matthew M.;Calaluce, Robert;Atasoy, Ulus
通讯作者：
Atasoy, Ulus