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Exosome-delivered microRNAs promote IFN-α secretion by human plasmacytoid DCs via TLR7
Valentina Salvi, … , Silvano Sozzani, Daniela Bosisio
Valentina Salvi, … , Silvano Sozzani, Daniela Bosisio
Published May 17, 2018
Citation Information: JCI Insight. 2018;3(10):e98204. https://doi.org/10.1172/jci.insight.98204.
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Research Article Immunology

Exosome-delivered microRNAs promote IFN-α secretion by human plasmacytoid DCs via TLR7

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Abstract

The excessive production of type I IFNs is a hallmark and a main pathogenic mechanism of many autoimmune diseases, including systemic lupus erythematosus (SLE). In these pathologies, the sustained secretion of type I IFNs is dependent on the improper activation of plasmacytoid DCs (pDCs) by self–nucleic acids. However, the nature and origin of pDC-activating self–nucleic acids is still incompletely characterized. Here, we report that exosomes isolated from the plasma of SLE patients can activate the secretion of IFN-α by human blood pDCs in vitro. This activation requires endosomal acidification and is recapitulated by microRNAs isolated from exosomes, suggesting that exosome-delivered microRNAs act as self-ligands of innate single-stranded endosomal RNA sensors. By using synthetic microRNAs, we identified an IFN induction motif that is responsible for the TLR7-dependent activation, maturation, and survival of human pDCs. These findings identify exosome-delivered microRNAs as potentially novel TLR7 endogenous ligands able to induce pDC activation in SLE patients. Therefore, microRNAs may represent novel pathogenic mediators in the onset of autoimmune reactions and potential therapeutic targets in the treatment of type I IFN–mediated diseases.

Authors

Valentina Salvi, Veronica Gianello, Sara Busatto, Paolo Bergese, Laura Andreoli, Ugo D’Oro, Alessandra Zingoni, Angela Tincani, Silvano Sozzani, Daniela Bosisio

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Figure 1

Exosomes from SLE plasma activate IFN-α secretion by pDCs.

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Exosomes from SLE plasma activate IFN-α secretion by pDCs.
(A) Represent...
(A) Representative AFM topography image of exosomes from systemic lupus erythematosus (SLE) plasma pools (scale bar: 500 nm; left). Particle size distribution obtained by image analysis of >1,200 round-shaped objects with a diameter ranging between 1 and 650 nm (5 μm × 5 μm fields, n = 6) demonstrating a prevailing exosome size (30–150 nm) (right). (B) Western blot of the exosome preparation showing the expression of exosome markers CD81 and CD63 and the lack of cis-Golgi matrix protein GM130 (negative control). One experiment out of 2 is represented; the lanes were run on the same gel but were noncontiguous. (C) pDCs from 4 donors were stimulated with exosomes purified from healthy or SLE plasma pools in the presence or absence of Chloroquine (CQ; 1 μM). The secretion of IFN-α was evaluated by ELISA after a 24-hour stimulation. Data are expressed as the mean ± SEM; *P < 0.05 versus (healthy) or #P < 0.05 versus (–) by paired Student’s t test. (D) Expression of selected microRNAs in exosomes obtained from plasma pools of healthy and SLE patients was evaluated by real-time PCR. Results were normalized over spiked-in cel-miR39. Data are expressed as the mean ± SEM of 3 replicates.

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