SNHG15 通过介导 TRAF2 泛素化在卒中诱导免疫抑制中作为炎症的负调节剂。

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

机构信息

General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, People's Republic of China.

Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, People's Republic of China.

出版信息

J Neuroinflammation. 2022 Jan 3;19(1):1. doi: 10.1186/s12974-021-02372-z.

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 .

背景

已有研究报道，长链非编码 RNA（lncRNA）在急性缺血性脑卒中（AIS）的急性期表达异常。本研究旨在探讨 AIS 患者外周血单个核细胞（PBMC）亚群中差异表达的 lncRNA，并进一步评估其在卒中诱导免疫抑制中的潜在机制。

方法

我们重新分析了 lncRNA 微阵列数据，并通过磁珠细胞分选和实时定量 PCR 研究了 PBMC 亚群中异常表达的 lncRNA。通过体外和体内方法探讨了小核仁 RNA 宿主基因 15（SNHG15）的潜在机制。

结果

卒中诱导的 SNHG15 作为抑制外周炎症反应的检查点。功能研究表明，SNHG15 促进 M2 巨噬细胞极化。机制上，SNHG15 通过 Janus 激酶（JAK）-信号转导和转录激活因子 6（STAT6）信号通路失调表达。SNHG15 定位于细胞质，干扰肿瘤坏死因子受体相关因子 2 的 K63 连接泛素化，从而抑制丝裂原活化蛋白激酶和核因子 κB 信号通路的激活，防止促炎细胞因子的产生。针对 SNHG15 的腺病毒给药可改善小鼠卒中诱导的免疫抑制。