SNHG15 is a negative regulator of inflammation by mediating TRAF2 ubiquitination in stroke-induced immunosuppression.

Abstract

BACKGROUND:

Abnormal expression of long noncoding RNAs (lncRNAs) has been reported in the acute stage of acute ischemic stroke (AIS). This study aimed to explore differential lncRNA expression in the subpopulations of peripheral blood mononuclear cells (PBMCs) from AIS patients and further evaluate its underlying mechanisms in stroke-induced immunosuppression.

METHODS:

We reanalyzed lncRNA microarray data and investigated abnormally expressed lncRNAs in the subpopulations of PBMCs by magnetic cell sorting and real-time quantitative PCR. The potential mechanism of small nucleolar RNA host gene 15 (SNHG15) was explored through in vitro and in vivo approaches.

RESULTS:

The stroke-induced SNHG15 acted as a checkpoint to inhibit peripheral inflammatory responses. Functional studies showed that SNHG15 promoted M2 macrophage polarization. Mechanistically, SNHG15 expression was dysregulated through the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) signaling pathway. SNHG15, localized in the cytoplasm, interfered with K63-linked ubiquitination of tumor necrosis factor receptor-associated factor 2 and thereby repressed the activation of mitogen-activated protein kinase and nuclear factor kappa-B signaling pathways and prevented the production of proinflammatory cytokines. Administration of an adenovirus targeting SNHG15 improved stroke-induced immunosuppression in mice.

CONCLUSIONS:

This study identified SNHG15 as a negative regulator of inflammation in stroke-induced immunosuppression, suggesting it as a novel biomarker and therapeutic target in stroke-associated infection. Trial registration ClinicalTrials.gov NCT04175691. Registered November 25, 2019, https://www.clinicaltrials.gov/ct2/show/NCT04175691 .

• Authors: Huiling Sun, Shuo Li, Zhaohan Xu, Chengfang Liu, Pengyu Gong, Qiwen Deng, Fuling Yan
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 19 Issue 1 Pg. 1 (Jan 03 2022) ISSN: 1742-2094 [Electronic] England
• PMID: 34980176 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• Cytokines
• Lipopolysaccharides
• RNA, Long Noncoding
• TNF Receptor-Associated Factor 2
• Interleukin-4

Topics

• Cytokines (metabolism)
• Humans
• Immune Tolerance
• Inflammation (immunology, metabolism)
• Interleukin-4 (pharmacology)
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects, metabolism)
• Monocytes (drug effects, metabolism)
• RNA, Long Noncoding (genetics, metabolism)
• Stroke (immunology, metabolism)
• TNF Receptor-Associated Factor 2 (genetics, metabolism)
• Ubiquitination