J Neuroinflammation|东南大学附属中大医院闫福岭团队揭示中风的分子调控机制

2022年8月3日 0条评论 321次阅读 0人点赞

最新细胞功能及机制文献分享

中风又名脑卒中，是全球成年人长期残疾和死亡的主要原因。脑卒中相关感染（SAI）是卒中后常见并发症之一，尤其是重度脑卒中，其会延长住院时间并增加死亡率。研究显示，在急性缺血性中风（AIS）的急性阶段，长链非编码RNA（lncRNAs）异常表达。

2022年1月3日，东南大学医学院附属中大医院神经内科闫福岭团队在Journal of Neuroinflammation上发表了题为“SNHG15 is a negative regulator of inflammation by mediating TRAF2 ubiquitination in stroke-induced immunosuppression”的研究论文。本研究旨在探讨AIS患者外周血单个核细胞（PBMC）亚群中lncRNAs的差异表达，并进一步评估其在卒中诱导的免疫抑制中的潜在机制。该研究将SNHG15鉴定为中风诱导的免疫抑制（SIIS）炎症的负调节因子，表明其是SAI的新型生物标志物和治疗靶点。

越来越多的临床和实验研究证据表明，SIIS可促使患者更容易受到中风后感染的影响。SIIS的特点是全身细胞免疫反应失衡，其作为SAI独立预测因子，表明免疫炎症反应在卒中后起重要作用。团队前期研究发现，缺血性卒中后交感神经通路增强，随后外周细胞因子水平发生显著变化。据报道，许多lncRNAs在缺血性中风中具有诊断和治疗价值，团队前期研究还表明，急性缺血性卒中患者外PBMC中lncRNAs存在差异表达，指出一组改变的lncRNA（linc-DHFRL1-4、SNHG15和linc-FAM98A-3）可作为新型诊断工具。

基于此，团队研究了这些lncRNAs在AIS后PBMC亚群中的差异表达谱，并通过细胞分选以及RT-PCR分析了PBMC亚群中异常表达的lncRNAs，提出IL-4介导的SNHG15通过抑制K63-TRAF2泛素化发挥抑炎因子的作用。具体内容为，体内外方法探索SNHG15潜在机制，发现中风诱导的SNHG15可作为抑制外周炎症反应的有效靶点。功能研究表明，SNHG15可促进M2巨噬细胞极化。机制上，SNHG15可介导JAK与STAT6信号通路。SNHG15位于细胞质中，可干扰K63关联的TRAF2泛素化，从而抑制MAPK和NF-κB信号通路的激活，并阻止促炎细胞因子的产生。最后，给予靶向SNHG15的腺病毒可改善小鼠SIIS。

《J Neuroinflammation|东南大学附属中大医院闫福岭团队揭示中风的分子调控机制》

图基于SNHG15中风诱发免疫抑制信号通路原理示意图。

期刊及DOI号

J Neuroinflammation. 2022 Jan 3.

doi: 10.1186/s12974-021-02372-z.

题目

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

摘要

背景：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.

方法：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.

结果：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.

结论：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.

关键词：Long noncoding RNA, Ischemic stroke, SNHG15, Immunosuppression, TRAF2