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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.

Original publication

DOI

10.1002/art.40225

Type

Journal article

Journal

Arthritis Rheumatol

Publication Date

11/2017

Volume

69

Pages

2124 - 2135

Keywords

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