title: MicroRNA miR-126-5p Enhances the Inflammatory Responses of Monocytes to Lipopolysaccharide Stimulation by Suppressing Cylindromatosis in Chronic HIV-1 Infection.
abstract: 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.IMPORTANCEMonocyte-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.
authors.affiliation: Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Xu
authors.affiliation: Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Linxia
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xiangqing
authors.initials: X
authors.lastname: Ding
authors.affiliation: Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Qibin
authors.initials: Q
authors.lastname: Liao
authors.affiliation: Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China xujianqing@shphc.org.cn zhangxiaoyan@shaphc.org.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China xujianqing@shphc.org.cn zhangxiaoyan@shaphc.org.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
mesh_terms: D002908:Chronic Disease; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007249:Inflammation; D008070:Lipopolysaccharides / Q000276:immunology*; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D008070:Lipopolysaccharides; C527111:MIRN126 microRNA, human; D035683:MicroRNAs; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD
keywords: CYLD; HIV-1; inflammatory responses; miR-126-5p; monocytes