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Cells Activation of Monocyte-Derived Dendritic Downregulate Lipopolysaccharide-Induced Neutrophil Extracellular Traps

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Cells Activation of Monocyte-Derived Dendritic Downregulate Lipopolysaccharide-Induced Neutrophil Extracellular Traps Neutrophil Extracellular Traps Downregulate Lipopolysaccharide-Induced Activation of Monocyte-Derived Dendritic Cells This information is current as of September 28, 2021. Lorena Barrientos, Alexandre Bignon, Claire Gueguen, Luc de Chaisemartin, Roseline Gorges, Catherine Sandré, Laurent Mascarell, Karl Balabanian, Saadia Kerdine-Römer, Marc Pallardy, Viviana Marin-Esteban and Sylvie Chollet-Martin Downloaded from J Immunol 2014; 193:5689-5698; Prepublished online 22 October 2014; doi: 10.4049/jimmunol.1400586 http://www.jimmunol.org/content/193/11/5689 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2014/10/19/jimmunol.140058 Material 6.DCSupplemental References This article cites 64 articles, 33 of which you can access for free at: http://www.jimmunol.org/content/193/11/5689.full#ref-list-1 by guest on September 28, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Neutrophil Extracellular Traps Downregulate Lipopolysaccharide-Induced Activation of Monocyte-Derived Dendritic Cells Lorena Barrientos,*,† Alexandre Bignon,*,‡,1 Claire Gueguen,x,1 Luc de Chaisemartin,*,†,{ Roseline Gorges,*,† Catherine Sandre´,*,† Laurent Mascarell,x Karl Balabanian,*,‡ Saadia Kerdine-Ro¨mer,*,† Marc Pallardy,*,† Viviana Marin-Esteban,*,†,2 and Sylvie Chollet-Martin*,†,{,2 Polymorphonuclear neutrophils (PMN) play a central role in inflammation and participate in its control, notably by modulating dendritic cell (DC) functions via soluble mediators or cell–cell contacts. Neutrophil extracellular traps (NETs) released by PMN Downloaded from could play a role in this context. To evaluate NET effects on DC maturation, we developed a model based on monocyte-derived DC (moDC) and calibrated NETs isolated from fresh human PMN. We found that isolated NETs alone had no discernable effect on moDC. In contrast, they downregulated LPS-induced moDC maturation, as shown by decreased surface expression of HLA-DR, CD80, CD83, and CD86, and by downregulated cytokine production (TNF-a, IL-6, IL-12, IL-23), with no increase in the expression of tolerogenic DC genes. Moreover, the presence of NETs during moDC maturation diminished the capacity of these moDC to induce T lymphocyte proliferation in both autologous and allogeneic conditions, and modulated CD4+ T lymphocyte http://www.jimmunol.org/ polarization by promoting the production of Th2 cytokines (IL-5 and IL-13) and reducing that of Th1 and Th17 cytokines (IFN-g and IL-17). Interestingly, the expression and activities of the lymphoid chemokine receptors CCR7 and CXCR4 on moDC were not altered when moDC matured in the presence of NETs. Together, these findings reveal a new role for NETs in adaptive immune responses, modulating some moDC functions and thereby participating in the control of inflammation. The Journal of Immu- nology, 2014, 193: 5689–5698. olymorphonuclear neutrophils (PMN) are the first line of of inflammation (3, 4) and pharmacological agents such as PMA antimicrobial defenses and are rapidly recruited to sites of and calcium ionophore (1, 3, 5–7). Netosis was initially described as P inflammation. PMN kill pathogens through various strat- a suicide-like mechanism, but a concept of “vital netosis” is also by guest on September 28, 2021 egies, including phagocytosis, degranulation, the oxidative burst, emerging (8). NETs are composed of extracellular chromatin dec- and release of neutrophil extracellular traps (NETs), a process orated with various granule-derived and cytoplasmic proteins. His- called netosis (1, 2). NETs are released by activated PMN in re- tones are the most abundant components [∼70% of total protein sponse to pathogenic bacteria, fungi, viruses, and protozoa (1, 3–5) (9)], but several important mediators of immune responses are also [reviewed in (6, 7)] and also in response to endogenous mediators present, such as elastase, lactoferrin, calprotectin, myeloperoxidase (MPO), and LL-37 [reviewed in (10)]. *INSERM, Unite´ Mixte de Recherche-S 996, “Cytokines, chimiokines et immunopa- The best-known function of NETs is pathogen trapping: this thologie,” Universite´ Paris-Sud, 92296 Chaˆtenay-Malabry and Clamart, France; property limits the dissemination of pathogens and exposes them † Universite´ Paris-Sud, Faculte´ de Pharmacie, 92296 Chaˆtenay-Malabry, France; to high local concentrations of various molecules immobilized on ‡Laboratory of Excellence in Research on Medication and Innovative Therapeutics, 92296 Clamart, France; xStallergenes, Antony Cedex 92183, France; and {Assistance the NET chromatin backbone (1, 7, 11) [reviewed in (12, 13)]. Publique Hoˆpitaux de Paris, Groupe Hospitalier Paris Nord Val de Seine, Hoˆpital However, NET accumulation can also have adverse consequences Bichat, Unite´ d’Immunologie (Auto-immunite´ et Hypersensibilite´s), 75018 Paris, France in in vitro and in vivo, such as epithelial and endothelial cell injury (6, 11, 14–16) and thrombus formation (17, 18) [reviewed in (10, 1A.B. and C.G. contributed equally to this work. 13)]. Moreover, by exposing self-Ags, NETs might be involved 2V.M.-E. and S.C.-M. contributed equally to this work. in autoimmune disorders, including small-vessel vasculitis, Received for publication March 5, 2014. Accepted for publication September 23, 2014. rheumatoid arthritis, type 1 diabetes, and systemic lupus ery- thematosus (SLE) (14, 19–21). In particular, during SLE, the This work was supported by an “Attractivite´” grant from Universite´ Paris-Sud. A.B. was the recipient of a fellowship from the French Ministry of Higher Education and association of self DNA with some PMN proteins (LL-37, ca- Research and from Fondation pour la Recherche Me´dicale (FDT20130928127). thepsin G, elastase, or secretory leukocyte peptidase inhibitor) Address correspondence and reprint requests to Prof. Sylvie Chollet-Martin, Unite´ induces IFN-a production by plasmacytoid dendritic cells (DC) Mixte de Recherche-S 996, Faculte´ de Pharmacie, 5 Rue J.B. Cle´ment, 92296 (22–25). This plasmacytoid DC/NETs/IFN-a axis could thus Chaˆtenay-Malabry Cedex, France. E-mail address: [email protected] represent an amplification loop of major importance in SLE The online version of this article contains supplemental material. pathogenesis (16, 23, 24) and illustrates how NETs can modulate Abbreviations used in this article: DC, dendritic cell; MFI, mean fluorescence inten- sity; MNase, micrococcal nuclease; moDC, monocyte-derived DC; MPO, myeloper- DC functions in vivo. Furthermore, on forming complexes with oxidase; NET, neutrophil extracellular trap; PI, propidium iodide; PMN, poly- RNA, these PMN proteins are able to activate myeloid DCs from morphonuclear neutrophil; rh, recombinant human; SLE, systemic lupus erythe- SLE patients, but not from controls (22, 24). matosus; TT, tetanus toxin C fragment. The role of PMN in DC functions is a growing field of inves- Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 tigation [reviewed in (26, 27)] and has been evaluated using blood www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400586 5690 NETs DOWNREGULATE DENDRITIC CELL ACTIVATION PMN or PMN-derived purified mediators. Activated PMN can negative fraction was kept for allogeneic T cell proliferation assays. Naive + promote DC migration (28) and also modulate DC maturation and CD4 T lymphocytes were also isolated from this fraction, by negative se- activation through cell–cell contacts (29), ectosome release (30), lection with the MACS naive CD4 isolation kit II (Miltenyi Biotec), to be used for Ag-specific T cell proliferation assays and polarization experiments. or mediator secretion. Interestingly, several granule-derived Total and naive CD4+ T lymphocytes were confirmed to have a purity .95%, mediators such as lactoferrin, LL-37, calprotectins, a-defensins, based on flow cytometry of CD4 and CD45RA expression, respectively. elastase, bactericidal/permeability-increasing protein, MPO, and NET production and isolation proteinase 3 have been shown to either downregulate (31–37) or upregulate (33, 38–41) DC functions, depending on the study. NETs were produced and isolated, as previously described (5). Briefly, 3 6 Few recent studies have evaluated the potential effects of NETs freshly isolated PMN were seeded in 12-well culture plates (1.5 10 cells/well) and stimulated with 5 mM A23187 for 3 h at 37˚C with 5% on APCs. Fully activated PMN bearing NETs can stimulate TNF-a CO2. The cells were carefully washed twice with 1 ml PBS and then and IL-8 release by THP-1 cells (42). NETs recovered after mi- treated for 20 min at 37˚C with 20 U/ml restriction enzyme AluI in HBSS crococcal nuclease treatment of activated PMN can enhance IL-1b to recover large soluble NET fragments.
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