Long non-coding RNA X-inactive specific transcript silencing ameliorates primary graft dysfunction following lung transplantation through microRNA-21-dependent mechanism.

Abstract

BACKGROUND:

Primary graft dysfunction (PGD) is a known acute lung injury (ALI) and a major cause of fatality post-lung transplantation. Though some long non-coding RNAs (lncRNAs) have been studied in ALI through regulation of microRNAs (miRNAs), their effects on PGD remain undefined. The present study aims to explore the underlying mechanism of lncRNA X-inactive specific transcript (XIST) in PGD after lung transplantation.

METHODS:

Initially, the expression of miR-21, IL-12A and XIST was determined by RT-qPCR and western blot analysis. The dual luciferase reporter assay, RNA pull-down and RIP assay were performed to identify the targeting relationship between miR-21 and IL-12A and the binding relationship between miR-21 and XIST. Loss- and gain-of-function investigations were conducted in rats treated with prolonged cold ischemia and polymorphonuclear neutrophils (PMNs).

FINDINGS:

miR-21 was decreased, whilst XIST and IL-12A were increased in the bronchoalveolar lavage fluid of PGD patients after lung transplantation. Enhanced miR-21 expression in rats and PMNs resulted in downregulated expression of pro-inflammatory factors and chemokines, and enhanced the apoptosis of PMNs. XIST was found to upregulate IL-12A expression in a miR-21-dependent manner. Additionally, XIST silencing enhanced the apoptosis of PMNs and inhibited the neutrophil extracellular trap (NET) formation through upregulation of miR-21 but downregulation of IL-12A in vivo.

INTERPRETATION:

In summary, lncRNA XIST upregulates IL-12A by binding to miR-21, thereby inducing NET formation and accelerating PGD after lung transplantation. This suggests that inhibition of XIST and NET may be beneficial for the treatment of PGD.

• Authors: Jiwei Li, Li Wei, Zhijun Han, Zhong Chen, Quan Zhang
• Journal: EBioMedicine (EBioMedicine) Vol. 52 Pg. 102600 (Feb 2020) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 31981974 (Publication Type: Journal Article)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• 3' Untranslated Regions
• Biomarkers
• Interleukin-12 Subunit p35
• MIRN21 microRNA, human
• MicroRNAs
• RNA, Long Noncoding
• RNA, Messenger
• XIST non-coding RNA
• mirn21 microRNA, rat

Topics

• 3' Untranslated Regions
• Animals
• Biomarkers
• Biopsy
• Extracellular Traps (genetics)
• Gene Expression Regulation
• Gene Silencing
• Humans
• Immunohistochemistry
• Interleukin-12 Subunit p35 (genetics)
• Lung Transplantation (adverse effects, methods)
• MicroRNAs (genetics)
• Models, Animal
• Primary Graft Dysfunction (etiology)
• RNA Interference
• RNA, Long Noncoding (genetics)
• RNA, Messenger
• Rats
• Transplantation, Homologous