HIV-1 gp120 influences the expression of microRNAs in human monocyte-derived dendritic cells via STAT3 activation

BMC Genomics

Sandra Gessani¹  Manuela Del Cornò¹  Barbara Varano¹  Letizia Da Sacco²  Gloria Donninelli¹  Andrea Masotti² 

[1] Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy;Bambino Gesù Children’s Hospital-IRCCS, Viale di San Paolo 15, Rome, 00146, Italy

关键词: gp120;    STAT3;    Dendritic cell;    HIV-1;    microRNA;   

Others  :  1219267
DOI  :  10.1186/s12864-015-1673-3

 received in 2015-01-28, accepted in 2015-05-29,  发布年份 2015

【 摘 要 】

Background

MicroRNAs (miRs) are an abundant class of small non-coding RNAs (~22 nt) that reprogram gene expression by targeting mRNA degradation and translational disruption. An emerging concept implicates miR coupling with transcription factors in myeloid cell development and function, thus contributing to host defense and inflammation. The important role that these molecules play in the pathogenesis of HIV-1 is only now emerging.

Results

We provide evidence that exposure of monocyte-derived dendritic cells (MDDCs) to recombinant HIV-1 R5 gp120, but not to CCR5 natural ligand CCL4, influences the expression of a panel of miRs (i.e., miR-21, miR-155 and miR-181b) regulated by STAT3 and potentially targeting genes belonging to the STAT3 signaling pathway. The blockage of gp120-induced STAT3 activation impairs gp120 capacity to modulate the expression level of above mentioned miRs. Predictive analysis of miR putative targets emphasizes that these miRs share common target genes. Furthermore, gene ontology and pathway enrichment analysis outline that these genes mainly belong to biological processes related to regulation of transcription, in a complex network of interactions involving pathways relevant to HIV-DC interaction.

Conclusions

Overall, these results point to gp120-triggered modulation of miR expression via STAT3 activation as a novel molecular mechanism exploited by HIV-1 to affect DC biology and thus modulate the immune response through complex regulatory loops involving, at the same time, miRs and transcription factors.

【 授权许可】

   
2015 Masotti et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Fig. 6.

【 参考文献 】

• [1]Guo YE, Steitz JA. Virus meets host microRNA: the destroyer, the booster, the hijacker. Mol Cell Biol. 2014; 34:3780-7.
• [2]Huang Y, Shen XJ, Zou Q, Wang SP, Tang SM, Zhang GZ. Biological functions of microRNAs: a review. J Physiol Biochem. 2011; 67:129-39.
• [3]Tsang J, Zhu J, van Oudenaarden A. MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. Mol Cell. 2007; 26:753-67.
• [4]Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science. 2005; 309:1577-81.
• [5]Lecellier CH, Dunoyer P, Arar K, Lehmann-Che J, Eyquem S, Himber C et al.. A cellular microRNA mediates antiviral defense in human cells. Science. 2005; 308:557-60.
• [6]Triboulet R, Benkirane M. Interplay between HIV-1 replication and the microRNA-silencing pathway. Med Sci. 2007; 23:590-2.
• [7]Yeung ML, Bennasser Y, Myers TG, Jiang G, Benkirane M, Jeang KT. Changes in microRNA expression profiles in HIV-1-transfected human cells. Retrovirology. 2005; 2:81-8. BioMed Central Full Text
• [8]Huang J, Wang F, Argyris E, Chen K, Liang Z, Tian H et al.. Cellular microRNAs contribute to HIV-1 latency in resting primary CD4 + T lymphocytes. Nat Med. 2007; 13:1241-7.
• [9]Swaminathan G, Navas-Martin S, Martin-Garcia J. MicroRNAs and HIV-1 infection: antiviral activities and beyond. J Mol Biol. 2014; 426:1178-97.
• [10]Witwer KW, Watson AK, Blankson JN, Clements JE. Relationships of PBMC microRNA expression, plasma viral load, and CD4 + T-cell count in HIV-1-infected elite suppressors and viremic patients. Retrovirology. 2012; 9:5-20. BioMed Central Full Text
• [11]Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 2013; 31:563-604.
• [12]Manches O, Frleta D, Bhardwaj N. Dendritic cells in progression and pathology of HIV infection. Trends Immunol. 2014; 35:114-22.
• [13]Chougnet C, Gessani S. Role of gp120 in dendritic cell dysfunction in HIV infection. J Leukoc Biol. 2006; 80:994-1000.
• [14]Del Corno M, Donninelli G, Varano B, Da Sacco L, Masotti A, Gessani S. HIV-1 gp120 activates the STAT3/interleukin-6 axis in primary human monocyte-derived dendritic cells. J Virol. 2014; 88:11045-55.
• [15]Cao Q, Li YY, He WF, Zhang ZZ, Zhou Q, Liu X et al.. Interplay between microRNAs and the STAT3 signaling pathway in human cancers. Physiol Genomics. 2013; 45:1206-14.
• [16]Rozovski U, Calin GA, Setoyama T, D’Abundo L, Harris DM, Li P et al.. Signal transducer and activator of transcription (STAT)-3 regulates microRNA gene expression in chronic lymphocytic leukemia cells. Mol Cancer. 2013; 12:50. BioMed Central Full Text
• [17]Pennisi E. Genomics. ENCODE project writes eulogy for junk DNA. Science. 2012; 337:1159-61.
• [18]Li P, Grgurevic S, Liu Z, Harris D, Rozovski U, Calin GA et al.. Signal transducer and activator of transcription-3 induces microRNA-155 expression in chronic lymphocytic leukemia. PLos One. 2013; 8:e64678.
• [19]Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell. 2010; 39:493-506.
• [20]Liu LH, Li H, Li JP, Zhong H, Zhang HC, Chen J et al.. miR-125b suppresses the proliferation and migration of osteosarcoma cells through down-regulation of STAT3. Biochem Biophys Res Commun. 2011; 416:31-8.
• [21]Matsuyama H, Suzuki HI, Nishimori H, Noguchi M, Yao T, Komatsu N et al.. miR-135b mediates NPM-ALK-driven oncogenicity and renders IL-17-producing immunophenotype to anaplastic large cell lymphoma. Blood. 2011; 118:6881-92.
• [22]Schust J, Sperl B, Hollis A, Mayer TU, Berg T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol. 2006; 13:1235-42.
• [23]Del Corno M, Michienzi A, Masotti A, Da Sacco L, Bottazzo GF, Belardelli F et al.. CC chemokine ligand 2 down-modulation by selected Toll-like receptor agonist combinations contributes to T helper 1 polarization in human dendritic cells. Blood. 2009; 114:796-806.
• [24]Ceppi M, Pereira PM, Dunand-Sauthier I, Barras E, Reith W, Santos MA et al.. MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci U S A. 2009; 106:2735-40.
• [25]Jin P, Han TH, Ren J, Saunders S, Wang E, Marincola FM et al.. Molecular signatures of maturing dendritic cells: implications for testing the quality of dendritic cell therapies. J Transl Med. 2010; 8:4-19. BioMed Central Full Text
• [26]Busch M, Zernecke A. microRNAs in the regulation of dendritic cell functions in inflammation and atherosclerosis. J Mol Med (Berl). 2012; 90:877-85.
• [27]Turner ML, Schnorfeil FM, Brocker T. MicroRNAs regulate dendritic cell differentiation and function. J Immunol. 2011; 187:3911-7.
• [28]Masotti A, Alisi A. Integrated bioinformatics analysis of microRNA expression profiles for an in-depth understanding of pathogenic mechanisms in non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2012; 27:187-8.
• [29]da Huang W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009; 37:1-13.
• [30]Anand AR, Prasad A, Bradley RR, Deol YS, Nagaraja T, Ren X et al.. HIV-1 gp120-induced migration of dendritic cells is regulated by a novel kinase cascade involving Pyk2, p38 MAP kinase, and LSP1. Blood. 2009; 114:3588-600.
• [31]Shan M, Klasse PJ, Banerjee K, Dey AK, Iyer SP, Dionisio R et al.. HIV-1 gp120 mannoses induce immunosuppressive responses from dendritic cells. PLoS Pathog. 2007; 3: Article ID e169
• [32]Klase Z, Houzet L, Jeang KT. MicroRNAs and HIV-1: complex interactions. J Biol Chem. 2012; 287:40884-90.
• [33]Bivalkar-Mehla S, Vakharia J, Mehla R, Abreha M, Kanwar JR, Tikoo A et al.. Viral RNA silencing suppressors (RSS): novel strategy of viruses to ablate the host RNA interference (RNAi) defense system. Virus Res. 2011; 155:1-9.
• [34]Triboulet R, Mari B, Lin YL, Chable-Bessia C, Bennasser Y, Lebrigand K et al.. Suppression of microRNA-silencing pathway by HIV-1 during virus replication. Science. 2007; 315:1579-82.
• [35]Patel P, Ansari M, Bapat S, Thakar M, Gangakhedkar R, Jameel S. The microRNA miR-29a is associated with human immunodeficiency virus latency. Retrovirology. 2014; 11:108-12. BioMed Central Full Text
• [36]Detsika MG, Psarris A, Paraskevis D. MicroRNAs and HIV latency: a complex and promising relationship. AIDS Rev. 2012; 14:188-94.
• [37]Bignami F, Pilotti E, Bertoncelli L, Ronzi P, Gulli M, Marmiroli N et al.. Stable changes in CD4+ T lymphocyte miRNA expression after exposure to HIV-1. Blood. 2012; 119:6259-67.
• [38]Wang X, Ye L, Hou W, Zhou Y, Wang YJ, Metzger DS et al.. Cellular microRNA expression correlates with susceptibility of monocytes/macrophages to HIV-1 infection. Blood. 2009; 113:671-4.
• [39]Orecchini E, Doria M, Michienzi A, Giuliani E, Vassena L, Ciafre SA et al.. The HIV-1 Tat protein modulates CD4 expression in human T cells through the induction of miR-222. RNA Biol. 2014; 11:334-8.
• [40]Fantuzzi L, Canini I, Belardelli F, Gessani S. HIV-1 gp120 stimulates the production of beta-chemokines in human peripheral blood monocytes through a CD4-independent mechanism. J Immunol. 2001; 166:5381-7.
• [41]Del Corno M, Liu QH, Schols D, de Clercq E, Gessani S, Freedman BD et al.. HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling. Blood. 2001; 98:2909-16.
• [42]Liu QH, Williams DA, McManus C, Baribaud F, Doms RW, Schols D et al.. HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation. Proc Natl Acad Sci U S A. 2000; 97:4832-7.
• [43]Fantuzzi L, Spadaro F, Purificato C, Cecchetti S, Podo F, Belardelli F et al.. Phosphatidylcholine-specific phospholipase C activation is required for CCR5-dependent, NF-kB-driven CCL2 secretion elicited in response to HIV-1 gp120 in human primary macrophages. Blood. 2008; 111:3355-63.
• [44]Spadaro F, Cecchetti S, Purificato C, Sabbatucci M, Podo F, Ramoni C et al.. Nuclear phosphoinositide-specific phospholipase C beta1 controls cytoplasmic CCL2 mRNA levels in HIV-1 gp120-stimulated primary human macrophages. PLos One. 2013; 8: Article ID e59705
• [45]Tomkowicz B, Lee C, Ravyn V, Cheung R, Ptasznik A, Collman RG. The Src kinase Lyn is required for CCR5 signaling in response to MIP-1beta and R5 HIV-1 gp120 in human macrophages. Blood. 2006; 108:1145-50.
• [46]Cheung R, Ravyn V, Wang L, Ptasznik A, Collman RG. Signaling mechanism of HIV-1 gp120 and virion-induced IL-1beta release in primary human macrophages. J Immunol. 2008; 180:6675-84.
• [47]Ohno M, Natsume A, Kondo Y, Iwamizu H, Motomura K, Toda H et al.. The modulation of microRNAs by type I IFN through the activation of signal transducers and activators of transcription 3 in human glioma. Mol Cancer Res. 2009; 7:2022-30.
• [48]Hashimi ST, Fulcher JA, Chang MH, Gov L, Wang S, Lee B. MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation. Blood. 2009; 114:404-14.
• [49]Fantuzzi L, Purificato C, Donato K, Belardelli F, Gessani S. Human immunodeficiency virus type 1 gp120 induces abnormal maturation and functional alterations of dendritic cells: a novel mechanism for AIDS pathogenesis. J Virol. 2004; 78:9763-72.
• [50]Martinez-Nunez RT, Louafi F, Friedmann PS, Sanchez-Elsner T. MicroRNA-155 modulates the pathogen binding ability of dendritic cells (DCs) by down-regulation of DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN). J Biol Chem. 2009; 284:16334-42.
• [51]Napuri J, Pilakka-Kanthikeel S, Raymond A, Agudelo M, Yndart-Arias A, Saxena SK et al.. Cocaine enhances HIV-1 infectivity in monocyte derived dendritic cells by suppressing microRNA-155. PLos One. 2013; 8:e83682.
• [52]Lu C, Huang X, Zhang X, Roensch K, Cao Q, Nakayama KI et al.. miR-221 and miR-155 regulate human dendritic cell development, apoptosis, and IL-12 production through targeting of p27kip1, KPC1, and SOCS-1. Blood. 2011; 117:4293-303.
• [53]Sun G, Li H, Wu X, Covarrubias M, Scherer L, Meinking K et al.. Interplay between HIV-1 infection and host microRNAs. Nucleic Acids Res. 2012; 40:2181-96.
• [54]Tao T, Wang Y, Luo H, Yao L, Wang L, Wang J et al.. Involvement of FOS-mediated miR-181b/miR-21 signalling in the progression of malignant gliomas. Eur J Cancer. 2013; 49:3055-63.
• [55]Ma X, Becker Buscaglia LE, Barker JR, Li Y. MicroRNAs in NF-kappaB signaling. J Mol Cell Biol. 2011; 3:159-66.
• [56]Sun X, Icli B, Wara AK, Belkin N, He S, Kobzik L et al.. MicroRNA-181b regulates NF-kappaB-mediated vascular inflammation. J Clin Invest. 2012; 122:1973-90.
• [57]O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A. 2007; 104:1604-9.
• [58]Sheedy FJ, Palsson-McDermott E, Hennessy EJ, Martin C, O’Leary JJ, Ruan Q et al.. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol. 2010; 11:141-7.
• [59]Pirvulescu M, Manduteanu I, Gan AM, Stan D, Simion V, Butoi E et al.. A novel pro-inflammatory mechanism of action of resistin in human endothelial cells: up-regulation of SOCS3 expression through STAT3 activation. Biochem Biophys Res Commun. 2012; 422:321-6.
• [60]Regis G, Pensa S, Boselli D, Novelli F, Poli V. Ups and downs: the STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling. Semin Cell Dev Biol. 2008; 19:351-9.
• [61]Lee C, Huang CH. LASAGNA-Search: an integrated web tool for transcription factor binding site search and visualization. BioTechniques. 2013; 54:141-53.
• [62]Dweep H, Sticht C, Pandey P, Gretz N. miRWalk–database: prediction of possible miRNA binding sites by “walking” the genes of three genomes. J Biomed Inform. 2011; 44:839-47.
• [63]Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT et al.. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 2005; 33: Article ID e179
• [64]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001; 25:402-8.
• [65]Wang Z, Han J, Cui Y, Zhou X, Fan K. miRNA-21 inhibition enhances RANTES and IP-10 release in MCF-7 via PIAS3 and STAT3 signalling and causes increased lymphocyte migration. Biochem Biophys Res Commun. 2013; 439:384-9.