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Therapeutic Modulation of Plasmacytoid Dendritic Cells in Experimental Arthritis
Author(s) -
Nehmar Ramzi,
Alsaleh Ghada,
Voisin Benjamin,
Flacher Vincent,
Mariotte Alexandre,
Saferding Victoria,
Puchner Antonia,
Niederreiter Birgit,
Vandamme Thierry,
Schabbauer Gernot,
Kastner Philippe,
Chan Susan,
Kirstetter Peggy,
Holcmann Martin,
Mueller Christopher,
Sibilia Jean,
Bahram Seiamak,
Blüml Stephan,
Georgel Philippe
Publication year - 2017
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40225
Subject(s) - arthritis , rheumatoid arthritis , medicine , inflammation , immunology , tlr7 , tumor necrosis factor alpha , cytokine , tlr9 , cancer research , toll like receptor , immune system , biology , innate immune system , biochemistry , gene expression , dna methylation , gene
Objective The role of plasmacytoid dendritic cells ( PDC s) and type I interferons ( IFN s) in rheumatoid arthritis ( RA ) remains a subject of controversy. This study was undertaken to explore the contribution of PDC s and type I IFN s 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 PDC s and type I IFN signaling. Our findings indicate that local recruitment and activation of PDC s represents an attractive therapeutic opportunity for RA patients.