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.

Transcriptome analysis of long non-coding RNAs in Mycobacterium avium complex–infected macrophages

“…In fact, we observed a radical decline in Bcl2l11 expression when Morrbid was upregulated ( Figure 7B ). Among the downregulated lncRNAs, eight had at least one citation; AI662270 , AU020206 , and Snhg15 were of particular interest ( Figure 7C ), as it has been reported that AI662270 and AU020206 are involved in the atherosclerosis induced by macrophages ( 33 , 34 ) and Snhg15 is involved in inflammation ( 35 ).…”

The relationship between red blood cell distribution width at admission and post-stroke fatigue in the acute phase of acute ischemic stroke

“…In normal Chinese population, the levels of RDW range from 11.0 to 16.0%, and may increase under pathological conditions. It is well known that inflammatory response plays a prominent role on the pathophysiology of cerebrovascular disease ( 17 – 22 ). RDW may be associated with C-reactive protein, interleukin −6 and other inflammatory biomarkers ( 23 , 24 ).…”

Crosstalk between ubiquitin ligases and ncRNAs drives cardiovascular disease progression

“…Moreover, circSCMH1 promotes translocation of obesity-associated protein into the endothelial cell nucleus via ubiquitination and subsequently facilitates m6A demethylation of Plpp3 mRNA and upregulates Plpp3 expression, thereby enhancing vascular repair after stroke in mice in vivo and in vitro ( 91 ). LncRNA SNHG15 suppressed K63-linked TRAF2 ubiquitination to improve acute ischemic stroke ( 92 ). Notably, in mouse ischemic stroke models (middle cerebral artery occlusion) in vivo , miR-181b expression is downregulated in response to ischemic exposure, thus ameliorating poststroke neurovascular injury by increasing ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) and HSPA5 expression ( 93 ).…”