复旦大学徐建青张晓燕课题组JVI揭示HIV慢性感染炎症调控关键分子
近日复旦大学附属上海市公共卫生临床中心徐建青张晓燕课题组在国际权威病毒学期刊Journal of Virology上发表论文揭示了HIV慢性感染炎症调控关键分子。
HIV-1慢性感染导致的持续免疫活化促进免疫失衡并加速疾病进展。微生物及其代谢产物的转位进入血液以及单核细胞的高水平的炎症应答被认为是持续免疫活化重要诱因。 在HIV慢性感染的过程中，miRNAs是否在调控单核细胞活化发挥了某种作用有待解明。
本研究发现miR-126-5p 是HIV慢性感染过程中单核细胞活化的一个重要的调控因子，部分下调CYLD (Cylindromatosis, CYLD) 因而启动JNK (Jun N-terminal kinase, JNK) 通路。HIV-1慢性感染者单核细胞中观察到miR-126-5p显著上调与 CYLD显著下调并存的现象，而抑制HIV-1慢性感染者单核细胞中的miR-126-5p 表达能够减轻LPS 刺激应答反应。功能获得分析证实miR-126-5p可下调CYLD，转而上调JNK 蛋白磷酸化并增强LPS诱导的炎症应答。 总之， 在HIV-1慢性感染的过程中，miR-126-5p可调控LPS刺激的单核细胞高炎反应。在单核细胞中抑制miR-126-5p却促进CYLD表达也许是一种遏制HIV-1慢性感染中单核细胞活化的可行性免疫干预策略。
2017 Mar 1. pii: JVI.02048-16. doi: 10.1128/JVI.02048-16.
MiR-126-5p enhances the inflammatory responses of monocytes to LPS stimulation by suppressing CYLD in chronic HIV-1 infection.
Abstract
Persistent immune activation during chronic human immunodeficiency virus-1 (HIV-1) infection facilitates immune dysfunction and thereby fuels disease progression. The translocation of bacterial derivatives into blood and the hyper-inflammatory responsiveness of monocytes have been considered important causative factors for persistent immune activation. Whether microRNAs (miRNAs) involve in regulating monocyte-mediated inflammatory responses during chronic HIV-1 infection remains elusive. In this study, we show that miR-126-5p functions as a positive regulator of monocyte-mediated inflammatory responses. Significantly increased miR-126-5p and decreased cylindromatosis (CYLD) were observed in primary monocytes from chronic HIV-1 patients. Inhibition of miR-126-5p in monocytes from chronic HIV-1 patients attenuated the responsiveness of these cells to lipopolysaccharide (LPS) stimulation. Gain-of-function assays confirmed that miR-126-5p could down-regulate CYLD, which in turn caused an up-regulation of phosphorylation of JNK protein (pJNK) and enhanced inflammatory responses of monocytes to LPS stimulation. Overall, miR-126-5p up-regulates the responsiveness of monocytes to LPS stimulation in chronic HIV-1 infection, and the suppression of miR-126-5p and the promotion of CYLD expression in primary monocytes may represent a practical immune intervention strategy to contain persistent inflammation in chronic HIV-1 infection.
IMPORTANCE
Monocyte-mediated hyper-inflammatory responses during chronic HIV-1 infection are important causative factors driving acquired immune deficiency syndrome (AIDS) progression; however, the underlying mechanism has not been fully addressed. We demonstrated that miR-126-5p, one of the most up-regulated miRNAs during chronic HIV-1 infection, could enhance the inflammatory responses of monocytes to LPS by suppressing the inhibitory protein CYLD and thereby unleashing the expression of pJNK in the LPS/toll-like receptor 4 (TLR4)/mitogen-activated protein kinase (MAPK) pathway. This observation reveals a new mechanism for HIV-1 pathogenesis, which could be targeted by immune intervention.
来源：上海市公共卫生临床中心
本期编辑：Tony