Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes.
Dendritic cells (DCs) are the most potent APCs. Whereas immature DCs down-regulate T-cell responses to induce/maintain immunologic tolerance, mature DCs promote immunity. To amplify their functions, DCs communicate with neighboring DCs through soluble mediators, cell-to-cell contact, and vesicle exchange. Transfer of nanovesicles (< 100 nm) derived from the endocytic pathway (termed exosomes) represents a novel mechanism of DC-to-DC communication. The facts that exosomes contain exosome-shuttle miRNAs and DC functions can be regulated by exogenous miRNAs, suggest that DC-to-DC interactions could be mediated through exosome-shuttle miRNAs, a hypothesis that remains to be tested. Importantly, the mechanism of transfer of exosome-shuttle miRNAs from the exosome lumen to the cytosol of target cells is unknown. Here, we demonstrate that DCs release exosomes with different miRNAs depending on the maturation of the DCs. By visualizing spontaneous transfer of exosomes between DCs, we demonstrate that exosomes fused with the target DCs, the latter followed by release of the exosome content into the DC cytosol. Importantly, exosome-shuttle miRNAs are functional, because they repress target mRNAs of acceptor DCs. Our findings unveil a mechanism of transfer of exosome-shuttle miRNAs between DCs and its role as a means of communication and posttranscriptional regulation between DCs.
Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, PA, USA.
Angela
A
Montecalvo
Adriana T
AT
Larregina
William J
WJ
Shufesky
Donna Beer
DB
Stolz
Mara L G
ML
Sullivan
Jenny M
JM
Karlsson
Catherine J
CJ
Baty
Gregory A
GA
Gibson
Geza
G
Erdos
Zhiliang
Z
Wang
Jadranka
J
Milosevic
Olga A
OA
Tkacheva
Sherrie J
SJ
Divito
Rick
R
Jordan
James
J
Lyons-Weiler
Simon C
SC
Watkins
Adrian E
AE
Morelli
D000818:Animals; D017951:Antigen Presentation; D015415:Biomarkers / Q000378:metabolism; D002450:Cell Communication; D003600:Cytosol / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D055354:Exosomes / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D008561:Membrane Fusion; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis
D015415:Biomarkers; D035683:MicroRNAs