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Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation

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Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation This information is current as Jérôme C. Martin, Kerstin Wolk, Gaëlle Bériou, Ahmed of September 25, 2021. Abidi, Ellen Witte-Händel, Cédric Louvet, Georgios Kokolakis, Lucile Drujont, Laure Dumoutier, Jean-Christophe Renauld, Robert Sabat and Régis Josien J Immunol 2017; 198:3671-3678; Prepublished online 29 March 2017; Downloaded from doi: 10.4049/jimmunol.1700021 http://www.jimmunol.org/content/198/9/3671 References This article cites 47 articles, 12 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/198/9/3671.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • 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 © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation Je´roˆme C. Martin,*,†,‡,x,1 Kerstin Wolk,{,‖,#,1 Gae¨lle Be´riou,*,† Ahmed Abidi,*,†,** Ellen Witte-Ha¨ndel,{,‖ Ce´dric Louvet,*,† Georgios Kokolakis,{ Lucile Drujont,*,† Laure Dumoutier,††,‡‡ Jean-Christophe Renauld,††,‡‡ Robert Sabat,{,‖,xx,2 and Re´gis Josien*,†,‡,x,2 Psoriasis is a chronic inflammatory disease resulting from dysregulated immune activation associated with a large local secretion of cytokines. Among them, IL-22 largely contributes to epithelial remodeling and inflammation through inhibiting the terminal differentiation of keratinocytes and inducing antimicrobial peptides and selected chemokines. The activity of IL-22 is regulated by IL-22 binding protein (IL-22BP); however, the expression and role of IL-22BP in psoriatic skin has remained unknown so far. Downloaded from Here we showed that nonaffected skin of psoriasis patients displayed lower expression of IL-22BP than skin of healthy controls. Furthermore, the strong IL-22 increase in lesional psoriatic skin was accompanied by a moderate induction of IL-22BP. To investigate the role of IL-22BP in controlling IL-22 during skin inflammation, we used imiquimod-induced skin disease in rodents and showed that rats with genetic IL-22BP deficiency (Il22ra22/2) displayed exacerbated disease that associated with enhanced expression of IL-22–inducible antimicrobial peptides. We further recapitulated these findings in mice injected with an anti–IL- 22BP neutralizing Ab. Hypothesizing that the IL-22/IL-22BP expression ratio reflects the level of bioactive IL-22 in psoriasis skin, http://www.jimmunol.org/ we found positive correlations with the expression of IL-22–inducible molecules (IL-20, IL-24, IL-36g, CXCL1, and BD2) in keratinocytes. Finally, we observed that serum IL-22/IL-22BP protein ratio strongly correlated with psoriasis severity. In con- clusion, we propose that although IL-22BP can control deleterious actions of IL-22 in the skin, its limited production prevents a sufficient neutralization of IL-22 and contributes to the development and maintenance of epidermal alterations in psoriasis. The Journal of Immunology, 2017, 198: 3671–3678. soriasis is a chronic inflammatory skin disease that affects cruitment of further immune cells into the skin to create a self- ∼2% of the Caucasian population (1). Typical macro- sustained inflammatory milieu. Moreover, the high keratinocyte P scopic skin alterations present as sharply demarcated, red, production of antimicrobial peptides prevents infections of the by guest on September 25, 2021 and slightly raised lesions with silver-whitish scales. It is gener- highly disturbed psoriatic epidermis. Among a range of immune ally acknowledged that these skin changes result from chronic mediators present in the psoriatic skin, an essential role for IL-23 dysregulated activation of the cutaneous immune system that—by and its downstream cytokine IL-17A in the maintenance of pso- secreted cytokines—alters the biology of local tissue cells (2, 3). riatic lesions has been recently confirmed by the dramatic clinical Epidermal keratinocytes respond by hyperproliferation and im- success of their therapeutic blockade in these patients (4–7). pairment of their terminal differentiation, leading to epidermal Another major IL-23 downstream cytokine is the IL-10 family thickening, hypogranularity, and hyperkeratosis. At the same time, member IL-22. IL-22 is also present in large quantities in psoriatic these cells secrete high amounts of chemokines enabling the re- lesions (8). Main producers of IL-22 include different CD4+ T cell *Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Europe´en des Sciences de la Transplantation et de l’Immunologie (IHU-Cesti) Proj- Universite´ de Nantes, 44093 Nantes Cedex 1, France; †Institut de Transplantation ect. The IHU-Cesti Project is also supported by Nantes Me´tropole and the Pays de la Urologie Ne´phrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes Cedex Loire region. J.C.M. was supported by a grant from Centre Hospitalier Universitaire 1, France; ‡Faculte´ de Me´decine, Universite´ de Nantes, 44093 Nantes Cedex 1, (CHU) Nantes (Appel d’Offre Interne 2013 RC14_0042); J.C.M. also received sup- France; xLaboratoire d’Immunologie, Centre Hospitalier Universitaire Nantes, port from CHU Nantes through Anne´e Supple´mentaire d’Internat. G.B. was sup- 44093 Nantes Cedex 1, France; {Psoriasis Research and Treatment Center, ported by the Pays de la Loire Region through the IMmunoBIOthe´rapies et Dermatology/Medical Immunology, University Hospital Charite´, D-10117 Berlin, Cellules Dendritiques Network. A.A. was supported by a French-Tunisian UTIQUE Germany; ‖Interdisciplinary Group of Molecular Immunopathology, University grant from the 2015 Hubert Curien program. K.W. and R.S. were supported by Grant Hospital Charite´, D-10117 Berlin, Germany; #Berlin-Brandenburg Center for Re- 01ZX1312A from the German Federal Ministry of Education and Research. generative Therapies, University Hospital Charite´, 13353 Berlin, Germany; Address correspondence and reprint requests to Dr. Je´roˆme C. Martin at the current **Faculte´ des Sciences Mathe´matiques, Physiques et Naturelles, Universite´ de address: Department of Oncological Science, Icahn School of Medicine at Mount Tunis El Manar, 2092 Tunis, Tunisia ††Ludwig Institute for Cancer Research, Sinai, 1470 Madison Avenue, New York, NY 10029, Prof. Re´gis Josien, INSERM B-1200 Brussels, Belgium; ‡‡Institut de Duve, Universite´ Catholique de Louvain, xx UMR1064-ITUN, CHU Nantes Hoˆtel Dieu, Universite´ de Nantes, 30 Boulevard Jean B-1200 Brussels, Belgium; and Research Center Immunosciences, University Monnet, 44093 Nantes Cedex 1, France, or Dr. Robert Sabat, Interdisciplinary Group Hospital Charite´, D-10117 Berlin, Germany of Molecular Immunopathology, Dermatology/Medical Immunology, University 1J.C.M. and K.W. contributed equally to this work and are cofirst authors. Hospital Charite´, Charite´platz 1, D-10117 Berlin, Germany. E-mail addresses: [email protected] (J.C.M.), [email protected] (R.J.), or robert. 2R.S. and R.J. contributed equally to this work and are colast authors. [email protected] (R.S.) ORCIDs: 0000-0002-7689-4130 (K.W.); 0000-0002-8042-7885 (G.K.); 0000-0003- Abbreviations used in this article: IL-22BP, IL-22 binding protein; IMID, immune- 1736-2131 (J.-C.R.); 0000-0001-7900-7413 (R.J.). mediated inflammatory disease; PASI, psoriasis area and severity index; qRT-PCR, Received for publication January 5, 2017. Accepted for publication March 1, 2017. quantitative RT-PCR. This work was supported by the National Research Agency via Investment into the Ó Future Program Grant ANR-10-IBHU-005 for the Institut-Hospitalo Universitaire–Centre Copyright 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700021 3672 IL-22BP LIMITS IL-22–DEPENDENT INFLAMMATION IN PSORIASIS populations and group 3 innate lymphoid cells (9). Because the 23 reagent (rodent samples) (both from Applied Biosystems) and the expression of the membrane IL-22R is restricted to epithelial/ StepOne Plus device (Applied Biosystems). Primers and double-labeled epithelioid cells (8), IL-22 assumes major cross-talk functions be- fluorescent probes were either self-designed (human IL-20, IL-22, IL-24, IL-22BP, and BD2) (26) or purchased from Applied Biosystems (all others). tween immune and epithelial cells, especially at body barriers (10, Expressions were normalized to HPRT using the 2-DD cycle threshold 11). By inducing antimicrobial peptides and proinflammatory che- method, and results were expressed in arbitrary units. mokines, as well as by inhibiting the terminal differentiation of ELISA keratinocytes, IL-22 has been shown to largely contribute to in- flammation and epithelial remodeling of the psoriatic
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