Therapeutic Modulation of Plasmacytoid Dendritic Cells in Experimental Arthritis

Arthritis Rheumatol. 2017 Nov;69(11):2124-2135. doi: 10.1002/art.40225.


Objective: The role of plasmacytoid dendritic cells (PDCs) and type I interferons (IFNs) in rheumatoid arthritis (RA) remains a subject of controversy. This study was undertaken to explore the contribution of PDCs and type I IFNs to RA pathogenesis using various animal models of PDC depletion and to monitor the effect of localized PDC recruitment and activation on joint inflammation and bone damage.

Methods: Mice with K/BxN serum-induced arthritis, collagen-induced arthritis, and human tumor necrosis factor transgene insertion were studied. Symptoms were evaluated by visual scoring, quantification of paw swelling, determination of cytokine levels by enzyme-linked immunosorbent assay, and histologic analysis. Imiquimod-dependent therapeutic effects were monitored by transcriptome analysis (using quantitative reverse transcriptase-polymerase chain reaction) and flow cytometric analysis of the periarticular tissue.

Results: PDC-deficient mice showed exacerbation of inflammatory and arthritis symptoms after arthritogenic serum transfer. In contrast, enhancing PDC recruitment and activation to arthritic joints by topical application of the Toll-like receptor 7 (TLR-7) agonist imiquimod significantly ameliorated arthritis in various mouse models. Imiquimod induced an IFN signature and led to reduced infiltration of inflammatory cells.

Conclusion: The therapeutic effects of imiquimod on joint inflammation and bone destruction are dependent on TLR-7 sensing by PDCs and type I IFN signaling. Our findings indicate that local recruitment and activation of PDCs represents an attractive therapeutic opportunity for RA patients.

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Aminoquinolines / pharmacology*
  • Animals
  • Arthritis, Experimental / genetics
  • Arthritis, Experimental / immunology*
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / immunology*
  • Cytokines / drug effects
  • Cytokines / immunology
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gene Expression Profiling
  • Humans
  • Ikaros Transcription Factor / genetics
  • Imiquimod
  • Interferon Type I / drug effects*
  • Interferon Type I / immunology
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptor 7 / genetics
  • Tumor Necrosis Factor-alpha / genetics


  • Adjuvants, Immunologic
  • Aminoquinolines
  • Cytokines
  • Interferon Type I
  • Membrane Glycoproteins
  • TNF protein, human
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • Tumor Necrosis Factor-alpha
  • Zfpn1a1 protein, mouse
  • Ikaros Transcription Factor
  • Imiquimod