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

Autor: Takahiro Ito, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski, Hidenobu Kojima, Kentaro Kadono, Kojiro Nakamura, Kenneth J. Dery, Hirofumi Hirao, Shoichi Kageyama, Fady M. Kaldas
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
medicine.medical_treatment
Medical Biochemistry and Metabolomics
Cathepsin G
Neutrophil Activation
ELAV-Like Protein 1
chemistry.chemical_compound
Mice
0302 clinical medicine
2.1 Biological and endogenous factors
Aetiology
Cells
Cultured
Cultured
Liver Disease
Liver Injury/Regeneration
Cytoprotection
medicine.anatomical_structure
Cytokine
Liver
Hepatocyte
Reperfusion Injury
Aconitate decarboxylase
030211 gastroenterology & hepatology
Original Article
medicine.symptom
Signal Transduction
Cells
1.1 Normal biological development and functioning
Chronic Liver Disease and Cirrhosis
Clinical Sciences
Immunology
Inflammation
Proinflammatory cytokine
03 medical and health sciences
Underpinning research
Genetics
medicine
Animals
Humans
Transplantation
Gastroenterology & Hepatology
Hepatology
Inflammatory and immune system
Macrophages
Organ Transplantation
Original Articles
Molecular biology
Liver Transplantation
Heme oxygenase
030104 developmental biology
chemistry
Digestive Diseases
Biomarkers
Heme Oxygenase-1
Zdroj: Hepatology (Baltimore, Md.)
Hepatology (Baltimore, Md.), vol 72, iss 3
ISSN: 1527-3350
0270-9139
Popis: Author(s): Dery, Kenneth J; Nakamura, Kojiro; Kadono, Kentaro; Hirao, Hirofumi; Kageyama, Shoichi; Ito, Takahiro; Kojima, Hidenobu; Kaldas, Fady M; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W | Abstract: Background and aimsIschemia-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 resultsIn 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 2nhours 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.ConclusionsThis 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.
Databáze: OpenAIRE
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