Huang Jun, Zhu Lingyan, Qiu Chao, Xu Xuan, Zhang Linxia, Ding Xiangqing, Liao Qibin, Xu Jianqing, Zhang Xiaoyan
Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
J Virol. 2017 Apr 28;91(10). doi: 10.1128/JVI.02048-16. Print 2017 May 15.
Persistent immune activation during chronic human immunodeficiency virus type 1 (HIV-1) infection facilitates immune dysfunction and thereby fuels disease progression. The translocation of bacterial derivatives into blood and the hyperinflammatory responsiveness of monocytes have been considered important causative factors for persistent immune activation. Whether microRNAs (miRNAs) are involved 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 miRNA 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 downregulate CYLD, which in turn caused an upregulation of phosphorylation of JNK protein (pJNK) and enhanced inflammatory responses of monocytes to LPS stimulation. Overall, miR-126-5p upregulates 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. Monocyte-mediated hyperinflammatory responses during chronic HIV-1 infection are important causative factors driving AIDS progression; however, the underlying mechanism has not been fully addressed. We demonstrated that miR-126-5p, one of the most upregulated 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/mitogen-activated protein kinase pathway. This observation reveals a new mechanism for HIV-1 pathogenesis, which could be targeted by immune intervention.
在慢性人类免疫缺陷病毒1型（HIV-1）感染期间，持续的免疫激活会促进免疫功能障碍，进而加速疾病进展。细菌衍生物向血液中的转移以及单核细胞的高炎症反应性被认为是持续免疫激活的重要致病因素。在慢性HIV-1感染期间，微小RNA（miRNA）是否参与调节单核细胞介导的炎症反应仍不清楚。在本研究中，我们表明miR-126-5p作为单核细胞介导的炎症反应的正调节因子发挥作用。在慢性HIV-1患者的原代单核细胞中观察到miRNA miR-126-5p显著增加，而圆柱瘤蛋白（CYLD）减少。抑制慢性HIV-1患者单核细胞中的miR-126-5p可减弱这些细胞对脂多糖（LPS）刺激的反应性。功能获得实验证实，miR-126-5p可下调CYLD，进而导致JNK蛋白磷酸化（pJNK）上调，并增强单核细胞对LPS刺激的炎症反应。总体而言，miR-126-5p上调慢性HIV-1感染中单核细胞对LPS刺激的反应性，抑制原代单核细胞中miR-126-5p并促进CYLD表达可能代表一种控制慢性HIV-1感染中持续炎症的实用免疫干预策略。慢性HIV-1感染期间单核细胞介导 的高炎症反应是推动艾滋病进展的重要致病因素；然而，其潜在机制尚未完全阐明。我们证明，miR-126-5p是慢性HIV-1感染期间上调最明显的miRNA之一，它可通过抑制抑制性蛋白CYLD来增强单核细胞对LPS的炎症反应，从而在LPS/ Toll样受体4/丝裂原活化蛋白激酶途径中释放pJNK的表达。这一观察结果揭示了HIV-1发病机制的一种新机制，可作为免疫干预的靶点。
