Ramzi Nehmar1, Ghada Alsaleh1, Benjamin Voisin2, Vincent Flacher2, Alexandre Mariotte1, Victoria Saferding3, Antonia Puchner3, Birgit Niederreiter3, Thierry Vandamme4, Gernot Schabbauer5, Philippe Kastner6, Susan Chan6, Peggy Kirstetter6, Martin Holcmann7, Christopher Mueller2, Jean Sibilia1, Seiamak Bahram1, Stephan Blüml3, Philippe Georgel1. 1. Université de Strasbourg, INSERM, IRM UMR-S 1109, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, and Fédération Hospitalo-Universitaire, OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, Strasbourg, France. 2. Université de Strasbourg, CNRS UPR 3572, Laboratory of Immunopathology and Therapeutic Chemistry/Laboratory of Excellence MEDALIS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France. 3. Internal Medicine 3, Medical University of Vienna, Vienna, Austria. 4. Université de Strasbourg, CNRS UMR 7199, Faculté de Pharmacie, Illkirch, France. 5. Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria. 6. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, INSERM U964, CNRS UMR 7104, Illkirch, France. 7. Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Abstract
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.
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 humantumor 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 RApatients.
Authors: Faye A H Cooles; Amy E Anderson; Andrew Skelton; Arthur G Pratt; Mariola S Kurowska-Stolarska; Iain McInnes; Catharien M U Hilkens; John D Isaacs Journal: Front Immunol Date: 2018-05-09 Impact factor: 7.561