Neutrophil extracellular traps exacerbate Th1‐mediated autoimmune responses in rheumatoid arthritis by promoting DC maturation

European Journal of Immunology - Tập 46 Số 11 - Trang 2542-2554 - 2016
Garyfalia Papadaki1,2, Konstantinos Kambas3, Christiana Choulaki1,2, Katerina Vlachou4,1,2, Ηλίας Δράκος5, George Βertsias1,2, Konstantinos Ritis3, Dimitrios T. Boumpas6,4,1,7, Paul R. Thompson8, Panayotis Verginis4,9, Prodromos Sidiropoulos2
1Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Greece
2Laboratory of Rheumatology, Autoimmunity and Inflammation, Faculty of Medicine, University of Crete, Heraklion, Greece
3Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece
4Biomedical Research Foundation, Academy of Athens, Athens, Greece
5Department of Pathology, University of Crete Medical School, Heraklion Crete, Greece
64th Department of Medicine Attikon University Hospital Athens Greece
7Joint Academic Rheumatology Program, National and Kapodestrian University of Athens, Athens, Greece
8Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA
9these authors contributed equally to this work

Tóm tắt

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.

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European Journal of Immunology

Tập 46 Số 11

2542-2554

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