Human Antigen R (HuR): A New Regulator of Heme Oxygenase‐1 Cytoprotection in Mouse and Human Liver Transplant Injury

BACKGROUND & 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 AU-rich-containing mRNAs, is required for hepatoprotection in LT. APPROACH & RESULTS: In 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; while HuR silencing caused negative regulation of HO-1, followed by enhanced cytotoxicity. Using HuR-inhibitor we showed that HuR likely regulates HO-1 via its 3'UTR and causes neutrophil activation (CD69+/Ly6G). HuR silencing in bone marrow-derived macrophages (BMM) 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 novel genes THY1, ACOD1 and PTGES. HuR but not HIF-1alpha 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 LC3B, a marker for autophagosome, under HO-1 regulation, suggesting a cytoprotective mechanism in hepatic IR. In clinical arm, hepatic biopsies from fifty-one LT patients were analyzed at 2h 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 sALT/sAST levels and improved post-LT survival. CONCLUSIONS: This translational study identifies HuR as a new regulator of HO-1-mediated cytoprotection in sterile liver inflammation and a novel biomarker of ischemic stress-resistance in LT.