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Published on: May 31, 2018
Extracellular microRNAs induce dendritic cell-dependent joint inflammation and potentiate osteoclast differentiation
Carolina Gaudenzi1, Tiziana Schioppa2, Mauro Passari1
1Department of Molecular and Translational Medicine, University of Brescia, Italy.
Objectives:
Monocyte-derived dendritic cells (DCs) are key players in the induction of inflammation, autoreactive T cell activation and loss of tolerance in rheumatoid arthritis (RA), but the precise mechanisms underlying their activation remain elusive. Here, we hypothesized that extracellular microRNAs released in RA synovial fluids may represent a novel, physiological stimulus triggering unwanted immune response via TLR8-expressing DC stimulation.
Methods:
Human monocyte-derived DCs were stimulated with a mixture of GU-rich miRNAs upregulated in RA tissues and released in synovial fluids (Ex-miRNAs). Activation of DCs was assessed in terms of NF-κB activation by Western blot, cytokine production by ELISA, T cell proliferation and polarization by allogeneic mixed lymphocyte reaction. DC differentiation into osteoclasts was evaluated in terms of tartrate-resistant acid phosphatase production and formation of resorption pits in dentine slices. Induction of joint inflammation in vivo was evaluated using a murine model of DC-induced arthritis. TLR7/8 involvement was assessed by specific inhibitors.
Results:
Ex-miRNAs activate DCs to secrete TNFα, induce joint inflammation, start an early autoimmune response and potentiate the differentiation of DCs into aggressive osteoclasts.
Conclusions:
This work represents a proof of concept that the pool of extracellular miRNAs overexpressed in RA joints can act as a physiological activator of inflammation via the stimulation of TLR8 expressed by human DCs, which in turn exert arthritogenic functions. In this scenario, pharmacological inhibition of TLR8 might offer a new therapeutic option to reduce inflammation and osteoclast-mediated bone destruction in RA.
Insights
Extracellular microRNAs in rheumatoid arthritis (RA) activate dendritic cells (DCs) via TLR8, driving inflammation and bone destruction. Targeting TLR8 could be a new RA therapy.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Monocyte-derived dendritic cells (DCs) are implicated in rheumatoid arthritis (RA) pathogenesis.
- Mechanisms of DC activation in RA remain unclear.
- Extracellular microRNAs (Ex-miRNAs) in RA synovial fluid may activate DCs.
Purpose of the Study:
- Investigate if Ex-miRNAs in RA synovial fluid activate DCs.
- Determine the role of TLR8 in Ex-miRNA-induced DC activation.
- Assess the impact of Ex-miRNA-activated DCs on inflammation and bone destruction.
Main Methods:
- Human monocyte-derived DCs stimulated with RA Ex-miRNAs.
- Assessed DC activation (NF-κB, cytokines), T cell responses, and osteoclast differentiation.
- Evaluated joint inflammation in a murine arthritis model.
- Utilized TLR7/8 inhibitors to assess pathway involvement.
Main Results:
- Ex-miRNAs activated DCs, leading to TNFα secretion.
- Ex-miRNAs induced joint inflammation and autoimmune responses in vivo.
- DCs stimulated by Ex-miRNAs promoted osteoclast differentiation and activity.
- TLR8 was identified as the key receptor mediating these effects.
Conclusions:
- Extracellular microRNAs in RA joints activate human DCs via TLR8.
- Activated DCs promote inflammation and osteoclast-mediated bone destruction.
- TLR8 inhibition presents a potential therapeutic strategy for RA.
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