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TLR3 Ligand Poly(I:C) Exerts Distinct Actions in Synovial Fibroblasts When Delivered by Extracellular Vesicles
Mojca Frank-Bertoncelj1, David S Pisetsky2,3, Christoph Kolling4
1Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Schlieren, Switzerland.
Frontiers in Immunology
|February 14, 2018
Summary
Extracellular vesicles (EVs) protect double-stranded RNA (dsRNA) from degradation and deliver it to synovial fibroblasts, promoting inflammation and preventing apoptosis in rheumatoid arthritis (RA). This suggests EVs amplify dsRNA
Area of Science:
- Immunology
- Molecular Biology
- Rheumatology
Background:
- Extracellular vesicles (EVs) and extracellular RNA are abundant in rheumatoid arthritis (RA) synovial joints.
- RNA can activate Toll-like receptor 3 (TLR3) signaling in RA synovial fibroblasts (SFs).
- EVs may contribute to RA pathogenesis by interacting with dsRNA, a TLR3 ligand.
Purpose of the Study:
- To investigate if EVs interact with dsRNA and modify its effects in arthritis.
- To model these interactions using EVs from stimulated monocytes and peripheral blood mononuclear cells.
- To analyze the impact on RA SFs.
Main Methods:
- Stimulation of U937 cells and peripheral blood mononuclear cells with Poly(I:C) (a dsRNA analog) to generate EVs.
- Characterization of Poly(I:C) EVs for size, Annexin V binding, and MAC-1 expression.
- Assessment of Poly(I:C) content, RNAse III protection, and delivery to SFs.
- Evaluation of gene responses and apoptosis in SFs upon Poly(I:C) EV treatment.
Main Results:
- Poly(I:C) EVs contain and protect dsRNA from degradation.
- Poly(I:C) EVs effectively deliver dsRNA to SFs, inducing proinflammatory and antiviral gene responses.
- Unlike direct Poly(I:C) delivery, Poly(I:C) EVs inhibit apoptosis in SFs, promoting cell survival.
- EV-mediated dsRNA delivery exhibits lower toxicity compared to liposome delivery.
Conclusions:
- EVs play a significant role in shielding extracellular dsRNA and modulating its biological activities.
- EVs can enhance the pathogenic potential of dsRNA in arthritis by promoting inflammation and cell survival.
- These findings highlight EVs as key mediators in amplifying dsRNA-induced pathogenicity in RA, potentially contributing to synovial stroma expansion.
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