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Human Antigen R (HuR): A Regulator of Heme Oxygenase‐1 Cytoprotection in Mouse and Human Liver Transplant Injury
Author(s) -
Dery Kenneth J.,
Nakamura Kojiro,
Kadono Kentaro,
Hirao Hirofumi,
Kageyama Shoichi,
Ito Takahiro,
Kojima Hidenobu,
Kaldas Fady M.,
Busuttil Ronald W.,
KupiecWeglinski Jerzy W.
Publication year - 2020
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31093
Subject(s) - heme oxygenase , cytoprotection , hepatoprotection , proinflammatory cytokine , gene silencing , biology , reperfusion injury , microbiology and biotechnology , inflammation , chemistry , immunology , heme , medicine , apoptosis , ischemia , biochemistry , glutathione , gene , enzyme
Background and Aims 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. Approach and Results 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. Conclusions 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.