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).
MicroRNA-155 (miR-155) has been involved in the response to inflammation in macrophages and lymphocytes. Here we show how miR-155 participates in the maturation of human dendritic cells (DC) and modulates pathogen binding by down-regulating DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN), after directly targeting the transcription factor PU.1. During the maturation of DCs, miR-155 increases up to 130-fold, whereas PU.1 protein levels decrease accordingly. We establish that human PU.1 is a direct target for miR-155 and localize the target sequence for miR-155 in the 3'-untranslated region of PU.1. Also, overexpression of miR-155 in the THP1 monocytic cell line decreases PU.1 protein levels and DC-SIGN at both the mRNA and protein levels. We prove a link between the down-regulation of PU.1 and reduced transcriptional activity of the DC-SIGN promoter, which is likely to be the basis for its reduced mRNA expression, after miR-155 overexpression. Finally, we show that, by reducing DC-SIGN in the cellular membrane, miR-155 is involved in regulating pathogen binding as dendritic cells exhibited the lower binding capacity for fungi and HIV protein gp-120 when the levels of miR-155 were higher. Thus, our results suggest a mechanism by which miR-155 regulates proteins involved in the cellular immune response against pathogens that could have clinical implications in the way pathogens enter the human organism.
Martinez-Nunez
Rocio T
RT
From the Division of Infection, Inflammation and Repair, University of Southampton School of Medicine, Southampton SO16 6YD, United Kingdom.
Louafi
Fethi
F
From the Division of Infection, Inflammation and Repair, University of Southampton School of Medicine, Southampton SO16 6YD, United Kingdom.
Friedmann
Peter S
PS
From the Division of Infection, Inflammation and Repair, University of Southampton School of Medicine, Southampton SO16 6YD, United Kingdom.
Sanchez-Elsner
Tilman
T
From the Division of Infection, Inflammation and Repair, University of Southampton School of Medicine, Southampton SO16 6YD, United Kingdom; Southampton General Hospital, Southampton SO16 6YD, United Kingdom. Electronic address: T.Sanchez-Elsner@soton.ac.uk.
D020413:3' Untranslated Regions / Q000235:genetics; D002176:Candida albicans / Q000276:immunology; D002177:Candidiasis / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000502:physiology*; D015536:Down-Regulation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism*; D035683:MicroRNAs / Q000276:immunology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology; D000099232:Proto-Oncogene Protein Spi-1; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D020413:3' Untranslated Regions; D015815:Cell Adhesion Molecules; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C524942:MIRN155 microRNA, human; C514793:gp120 protein, Human immunodeficiency virus 1