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

• Published in: Cell death and differentiation Vol. 27; no. 1; pp. 176 - 191
• Main Authors: Wan, Peixing, Su, Wenru, Zhang, Yingying, Li, Zhidong, Deng, Caibin, Li, Jinmiao, Jiang, Nan, Huang, Siyu, Long, Erping, Zhuo, Yehong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2020; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/21; 13/31; 14/19; 38/61; 42/44; 631/208/176; 631/250/1933; 631/250/256/2177; 631/378/2596/1953; 64/60; Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biochemistry; Biomedical and Life Sciences; Caspases - metabolism; Cell Biology; Cell Cycle Analysis; Cytokines; Inflammasomes; Inflammasomes - metabolism; Inflammation; Ischemia; Life Sciences; Male; Membrane Potential, Mitochondrial; Mice, Inbred C57BL; Mice, Knockout; Microglia - pathology; MicroRNAs - metabolism; Mitochondria - metabolism; Neurons - pathology; Non-coding RNA; Pyroptosis; Reperfusion; Reperfusion Injury - genetics; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - physiopathology; Retina; Retina - metabolism; Retina - pathology; Retinal Diseases - genetics; Retinal Diseases - metabolism; Retinal Diseases - pathology; Retinal Diseases - physiopathology; Retinal Ganglion Cells - pathology; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Long Noncoding - physiology; Signal Transduction; Stem Cells; Transcriptome
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-019-0351-4

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.