长链非编码RNA SNHG15在脑卒中后外周免疫抑制中的作用及机制研究

Stroke-associated infection (SAI) is one of the most common complications of stroke, which can seriously influence the prognosis of patients. So far, the molecular mechanism of SAI is still poorly understood. Amount evidence has shown that stroke-induced peripheral immunosuppression is an important cause for SAI. Our preliminary work has found that IL-4 level is significantly upregulation in patients with stroke. SNHG15 expression was increased in stroke monocytes. Transcription factor STAT6 promoted SNHG15 expression. Function studies have shown that SNHG15 significantly inhibited M1 polarization of monocytes and macrophages. Its potential mechanism suggested that high SNHG15 expression inhibited K63 polyubiquitination of TRAF2, which was involved in the inhibition of NF-κB/MAPK signal pathways. Therefore, this project raised a scientific hypothesis: IL-4/STAT6-induced high expression of SNHG15 inhibited K63 polyubiquitination of TRAF2 and further suppressed the activation of NF-κB/MAPK signal pathways, which inhibited M1 polarization of monocytes and macrophages aggravating peripheral immunosuppression to promote the incidence of SAI. The project will perform clinical, cell and animal experiments to validate this hypothesis. The project will provide experimental evidence for molecular mechanism and available preventive and therapeutic measures of SAI.

卒中相关性感染（SAI）是脑卒中常见并发症之一，严重影响其预后。迄今，SAI发生的生物学机制尚不清楚。有研究表明：脑卒中后外周免疫抑制是SAI的重要原因。申请人前期研究表明：脑卒中后IL-4显著上调，单核细胞中SNHG15异常高表达；并初步探明转录因子STAT6促进SNHG15高表达；功能研究显示SNHG15显著抑制单核巨噬细胞向M1型极化，其潜在机制是高表达的SNHG15通过抑制TRAF2的K63多聚泛素化途径，抑制NF-κB/MAPK信号通路的活化。因此，本项目提出科研假说：脑卒中后IL-4/STAT6上调SNHG15表达后抑制TRAF2的K63多聚泛素化，进而抑制NF-κB/MAPK通路的活化，从而抑制单核巨噬细胞向M1促炎型态极化，加重免疫抑制，促进SAI的发生。本项目拟从临床和细胞动物层面验证上述假说。本项目的顺利完成为阐明SAI发生的生物学机制及有效防治措施提供新的实验依据。

卒中相关性感染（stroke-associated infection, SAI）是脑卒中尤其是重症脑卒中患者最常见的并发症之一，目前对SAI尚缺乏精准的早期预测指标及有效的防治策略。众多研究显示缺血性脑卒中（ischemic stroke，IS）可诱导免疫抑制综合征（stroke-induced immunodeficiency syndrome，SIDS），表现为单核细胞功能障碍与淋巴细胞减少，并显著增加了SAI的风险。长链非编码RNA（lncRNAs）已被报道在急性缺血性卒中（AIS）异常表达。本项目通过前期芯片数据及后续的样本验证发现SNHG15在PBMCs的单核巨噬细胞亚群中发挥主导作用。其次，PBMCs单核细胞中SNHG15的表达与脑卒中后外周免疫抑制密切相关；最后，通过体内外实验证实脑卒中后IL-4显著上调，单核细胞中SNHG15异常高表达；且转录因子STAT6促进SNHG15高表达；功能研究显示SNHG15显著抑制单核巨噬细胞向M1型极化，其潜在机制是高表达的SNHG15通过抑制TRAF2的K63多聚泛素化途径，抑制NF-κB/MAPK信号通路的活化。因此，本项目为阐明SAI发生的生物学机制及有效防治措施提供新的实验依据。