LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury

Peixing Wan,Zhidong Li,Nan Jiang,Wenru Su,Yingying Zhang,Caibin Deng,Jinmiao Li,Erping Long,Siyu Huang,Yehong Zhuo

doi:10.1038/s41418-019-0351-4

Abstract

Ischemia-reperfusion (I/R) is a common pathology when the blood supply to an organ was disrupted and then restored. During the reperfusion process, inflammation and tissue injury were triggered, which were mediated by immunocytes and cytokines. However, the mechanisms initiating I/R-induced inflammation and driving immunocytes activation remained largely unknown. In this study, we identified long non-coding RNA (lncRNA)-H19 as the key onset of I/R-induced inflammation. We found that I/R increased lncRNA-H19 expression to significantly promote NLRP3/6 inflammasome imbalance and resulted in microglial pyroptosis, cytokines overproduction, and neuronal death. These damages were effectively inhibited by lncRNA-H19 knockout. Specifically, lncRNA-H19 functioned via sponging miR-21 to facilitate PDCD4 expression and formed a competing endogenous RNA network (ceRNET) in ischemic cascade. LncRNA H19/miR-21/PDCD4 ceRNET can directly regulate I/R-induced sterile inflammation and neuronal lesion in vivo. We thus propose that lncRNA-H19 is a previously unknown danger signals in the molecular and immunological pathways of I/R injury, and pharmacological approaches to inhibit H19 seem likely to become treatment modalities for patients in the near future based on these mechanistic findings.

Highlights

Ischemia and reperfusion (I/R) is a common pathological condition characterized by an initial restriction of blood supply and followed by the subsequent restoration of perfusion
We identified long non-coding RNA (lncRNA)-H19 as a crucial player and uncovered its specific mechanism in retinal I/R, which can potentially serve as a therapeutic target
We found 618 significantly aberrant lncRNAs (P < 0.05 by the Wilcoxon signed-rank test) among I/R retinas

Summary

Introduction

Ischemia and reperfusion (I/R) is a common pathological condition characterized by an initial restriction of blood supply and followed by the subsequent restoration of perfusion. LncRNAs emerge as a breakthrough of deciphering molecular mechanisms underlying I/R-induced inflammation and serve as a potential therapeutic target. The. ceRNET facilitates coordination between lncRNAs and coding genes in various molecular signals by forming large-scale regulatory circuitries across the transcriptome [9] in biological and pathological processes [10,11,12,13]. LncRNA-H19 functioned through forming a ceRNET with miR-21 and PDCD4 to regulate NLRP3/6 inflammasome balance, pyroptosis and sterile inflammation. This ceRNET directly modulate neuronal death and mitochondrial dysfunction. These findings provide novel insights into the mechanisms of I/R injury and facilitated prophylaxis and treatment of I/R-mediated diseases

Results

Discussion

Methods

Compliance with ethical standards