title: Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation.
abstract: 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. 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 (Il22ra2-/-) 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, we found positive correlations with the expression of IL-22-inducible molecules (IL-20, IL-24, IL-36γ, CXCL1, and BD2) in keratinocytes. Finally, we observed that serum IL-22/IL-22BP protein ratio strongly correlated with psoriasis severity. In conclusion, 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.
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, 44093 Nantes Cedex 1, France; jerome.martin@mssm.edu regis.josien@univ-nantes.fr robert.sabat@charite.de.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes Cedex 1, France.|Faculté de Médecine, Université de Nantes, 44093 Nantes Cedex 1, France.|Laboratoire d'Immunologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes Cedex 1, France.
authors.forename: Jérôme C
authors.initials: JC
authors.lastname: Martin
authors.affiliation: Psoriasis Research and Treatment Center, Dermatology/Medical Immunology, University Hospital Charité, D-10117 Berlin, Germany.|Interdisciplinary Group of Molecular Immunopathology, University Hospital Charité, D-10117 Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies, University Hospital Charité, 13353 Berlin, Germany.
authors.forename: Kerstin
authors.identifier: 0000-0002-7689-4130
authors.initials: K
authors.lastname: Wolk
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, 44093 Nantes Cedex 1, France.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes Cedex 1, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bériou
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, 44093 Nantes Cedex 1, France.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes Cedex 1, France.|Faculté des Sciences Mathématiques, Physiques et Naturelles, Université de Tunis El Manar, 2092 Tunis, Tunisia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abidi
authors.affiliation: Psoriasis Research and Treatment Center, Dermatology/Medical Immunology, University Hospital Charité, D-10117 Berlin, Germany.|Interdisciplinary Group of Molecular Immunopathology, University Hospital Charité, D-10117 Berlin, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Witte-Händel
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, 44093 Nantes Cedex 1, France.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes Cedex 1, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Louvet
authors.affiliation: Psoriasis Research and Treatment Center, Dermatology/Medical Immunology, University Hospital Charité, D-10117 Berlin, Germany.
authors.forename: Georgios
authors.identifier: 0000-0002-8042-7885
authors.initials: G
authors.lastname: Kokolakis
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, 44093 Nantes Cedex 1, France.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes Cedex 1, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Drujont
authors.affiliation: Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium.|Institut de Duve, Université Catholique de Louvain, B-1200 Brussels, Belgium; and.
authors.forename: Laure
authors.initials: L
authors.lastname: Dumoutier
authors.affiliation: Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium.|Institut de Duve, Université Catholique de Louvain, B-1200 Brussels, Belgium; and.
authors.forename: Jean-Christophe
authors.identifier: 0000-0003-1736-2131
authors.initials: JC
authors.lastname: Renauld
authors.affiliation: Psoriasis Research and Treatment Center, Dermatology/Medical Immunology, University Hospital Charité, D-10117 Berlin, Germany; jerome.martin@mssm.edu regis.josien@univ-nantes.fr robert.sabat@charite.de.|Interdisciplinary Group of Molecular Immunopathology, University Hospital Charité, D-10117 Berlin, Germany.|Research Center Immunosciences, University Hospital Charité, D-10117 Berlin, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Sabat
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, 44093 Nantes Cedex 1, France; jerome.martin@mssm.edu regis.josien@univ-nantes.fr robert.sabat@charite.de.|Institut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes Cedex 1, France.|Faculté de Médecine, Université de Nantes, 44093 Nantes Cedex 1, France.|Laboratoire d'Immunologie, Centre Hospitalier Universitaire Nantes, 44093 Nantes Cedex 1, France.
authors.forename: Régis
authors.identifier: 0000-0001-7900-7413
authors.initials: R
authors.lastname: Josien
mesh_terms: D000328:Adult; D000368:Aged; D000634:Aminoquinolines; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D002478:Cells, Cultured; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D000077271:Imiquimod; D007249:Inflammation / Q000276:immunology*; D007378:Interleukins / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011565:Psoriasis / Q000139:chemically induced / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000276:immunology*; D055815:Young Adult; D000097043:Interleukin-22
chemical_list: D000634:Aminoquinolines; D019138:Antibodies, Blocking; D000077271:Imiquimod; D007378:Interleukins; D018123:Receptors, Interleukin; D000097043:Interleukin-22; C433253:IL22RA2 protein, human; C415369:interleukin-22 receptor