title: Depletion of regulatory T cells leads to an exacerbation of delayed-type hypersensitivity arthritis in C57BL/6 mice that can be counteracted by IL-17 blockade.
abstract: Rodent models of arthritis have been extensively used in the elucidation of rheumatoid arthritis (RA) pathogenesis and are instrumental in the development of therapeutic strategies. Here we utilise delayed-type hypersensitivity arthritis (DTHA), a model in C57BL/6 mice affecting one paw with synchronised onset, 100% penetrance and low variation. We investigate the role of regulatory T cells (Tregs) in DTHA through selective depletion of Tregsand the role of IL-17 in connection with Tregdepletion. Given the relevance of Tregsin RA, and the possibility of developing Treg-directed therapies, this approach could be relevant for advancing the understanding of Tregsin inflammatory arthritis. Selective depletion of Tregswas achieved using aFoxp3-DTR-eGFPmouse, which expresses the diphtheria toxin receptor (DTR) and enhanced green fluorescent protein (eGFP) under control of theFoxp3gene. Anti-IL-17 monoclonal antibody (mAb) was used for IL-17 blockade. Numbers and activation of Tregsincreased in the paw and its draining lymph node in DTHA, and depletion of Tregsresulted in exacerbation of disease as shown by increased paw swelling, increased infiltration of inflammatory cells, increased bone remodelling and increased production of inflammatory mediators, as well as increased production of anti-citrullinated protein antibodies. Anti-IL-17 mAb treatment demonstrated that IL-17 is important for disease severity in both the presence and absence of Tregs, and that IL-17 blockade is able to rescue mice from the exacerbated disease caused by Tregdepletion and caused a reduction in RANKL, IL-6 and the number of neutrophils. We show that Tregsare important for the containment of inflammation and bone remodelling in DTHA. To our knowledge, this is the first study using theFoxp3-DTR-eGFPmouse on a C57BL/6 background for Tregdepletion in an arthritis model, and we here demonstrate the usefulness of the approach to study the role of Tregsand IL-17 in arthritis.
authors.affiliation: Department of Diabetes Complications Research, Global Research, Novo Nordisk A/S, Maaloev 2760, Denmark Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg 1870, Denmark sara.marie.atkinson@gmail.com.
authors.forename: Sara Marie
authors.initials: SM
authors.lastname: Atkinson
authors.affiliation: Experimentelle Rheumatologie, Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hoffmann
authors.affiliation: Experimentelle Rheumatologie, Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
authors.affiliation: Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen 2100, Denmark.
authors.forename: Emil
authors.initials: E
authors.lastname: Bach
authors.affiliation: Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen 2100, Denmark.
authors.forename: Niels Banhos
authors.initials: NB
authors.lastname: Danneskiold-Samsøe
authors.affiliation: Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen 2100, Denmark.
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
authors.affiliation: Benaroya Research Institute, Seattle, WA 98101, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Serikawa
authors.affiliation: Immunexpress, Seattle, WA 98109, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Fox
authors.affiliation: Department of Diabetes Complications Research, Global Research, Novo Nordisk A/S, Maaloev 2760, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Kruse
authors.affiliation: Department of Diabetes Complications Research, Global Research, Novo Nordisk A/S, Maaloev 2760, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Haase
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg 1870, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Skov
authors.affiliation: Department of Pharmacology, Zealand Pharma, Glostrup 2600, Denmark.
authors.forename: Anneline
authors.initials: A
authors.lastname: Nansen
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D001775:Blood Circulation; D049109:Cell Proliferation; D018450:Disease Progression; D005121:Extremities / Q000473:pathology; D005243:Feces / Q000382:microbiology; D005260:Female; D006968:Hypersensitivity, Delayed / Q000276:immunology* / Q000473:pathology*; D007249:Inflammation / Q000473:pathology; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D008212:Lymphocyte Depletion; D008810:Mice, Inbred C57BL; D064307:Microbiota; D010641:Phenotype; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000382:microbiology
chemical_list: D015415:Biomarkers; D020381:Interleukin-17; D016753:Interleukin-10
keywords: ACPA; C57BL/6; IL-17; Microbiota; Neutrophils; Regulatory T cells; Rheumatoid arthritis
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