@article{3001307,
    title = "Neutrophil extracellular traps exacerbate Th1-mediated autoimmune responses in rheumatoid arthritis by promoting DC maturation",
    author = "Papadaki, G. and Kambas, K. and Choulaki, C. and Vlachou, K. and Drakos, E. and Bertsias, G. and Ritis, K. and Boumpas, D.T. and Thompson, P.R. and Verginis, P. and Sidiropoulos, P.",
    journal = "European Journal of Immunology",
    year = "2016",
    volume = "46",
    number = "11",
    pages = "2542-2554",
    publisher = "Wiley-VCH Verlag",
    issn = "0014-2980, 1521-4141",
    doi = "10.1002/eji.201646542",
    keywords = "collagen antibody;  collagen type 2;  DNA;  interleukin 17;  interleukin 6;  protein arginine deiminase;  collagen;  gamma interferon;  hydrolase;  interleukin 6;  interleukin-6, mouse;  N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide;  ornithine;  peptidylarginine deiminase 4, mouse, adult;  animal tissue;  arthritis;  Article;  attenuation;  autoimmunity;  CD4+ T lymphocyte;  cell maturation;  clinical article;  controlled study;  cytokine release;  dendritic cell;  disease activity;  enzyme activity;  enzyme inhibition;  extracellular trap;  female;  flow cytometry;  human;  in vitro study;  lymph node;  lymphocyte proliferation;  male;  middle aged;  molecule;  mouse;  nonhuman;  polarization;  priority journal;  rheumatoid arthritis;  T lymphocyte activation;  Th1 cell;  Th17 cell;  upregulation;  analogs and derivatives;  animal;  cell differentiation;  DBA mouse;  dendritic cell;  disease model;  drug effects;  experimental arthritis;  extracellular trap;  immunology;  metabolism;  pathophysiology;  rheumatoid arthritis;  secretion (process), Animals;  Arthritis, Experimental;  Arthritis, Rheumatoid;  Autoimmunity;  Cell Differentiation;  Collagen;  Dendritic Cells;  Disease Models, Animal;  Extracellular Traps;  Humans;  Hydrolases;  Interferon-gamma;  Interleukin-6;  Mice;  Mice, Inbred DBA;  Ornithine;  Th1 Cells",
    abstract = "Aberrant formation of neutrophil extracellular traps (NETs) is a key feature in rheumatoid arthritis (RA) and plays a pivotal role in disease pathogenesis. However, the mechanism through which NETs shape the autoimmune response in RA remains elusive. In this study, we demonstrate that inhibition of peptidylarginine deiminases activity in collagen-induced arthritis (CIA) mouse model significantly reduces NET formation, attenuates clinical disease activity, and prevents joint destruction. Importantly, peptidylarginine deiminase 4 blocking markedly reduces the frequency of collagen-specific IFN-γ-producing T helper 1 (Th1) cells in the draining lymph nodes of immunized mice. Exposure of dendritic cells (DCs) to CIA-derived NETs induces DC maturation characterized by significant upregulation of costimulatory molecules, as well as elevated secretion of IL-6. Moreover, CIA-NET-treated DCs promote the induction of antigen-specific Th1 cells in vitro. Finally, NETs from RA patients show an increased potential to induce the maturation of DCs from healthy individuals, corroborating the findings obtained in CIA mouse model. Collectively, our findings delineate an important role of NETs in the induction and expansion of Th1 pathogenic cells in CIA through maturation of DCs and reveal a novel role of NETs in shaping the RA-autoimmune response that could be exploited therapeutically. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim"
}