title: Langerin(neg) conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice.
abstract: Psoriasis is an autoinflammatory skin disease of unknown etiology. Topical application of Aldara cream containing the Toll-like receptor (TLR)7 agonist Imiquimod (IMQ) onto patients induces flares of psoriasis. Likewise, in mice IMQ triggers pathological changes closely resembling psoriatic plaque formation. Key cytokines like IL-23 and type-I IFN (IFN-I), both being produced mainly by dendritic cells (DCs), have been implicated in psoriasis. Although plasmacytoid DCs (pDCs) are the main source of IFNα and thought to initiate disease, conventional DCs (cDCs) appear to maintain the psoriatic lesions. Any role of cDCs during lesion formation remains elusive. Here, we report that selective activation of TLR7 signaling specifically in CD11c(+) DCs was sufficient to induce psoriasiform skin disease in mice. Intriguingly, both pDCs and the IFN-I pathway were dispensable for the development of local skin inflammation. Selective TLR7 triggering of Langerin(+) DCs resulted in attenuated disease, whereas their depletion did not alter the severity of skin lesions. Moreover, after IMQ-painting, IL-23 was exclusively produced by Langerin(neg) DCs in vivo. In conclusion, TLR7-activated Langerin(neg) cDCs trigger psoriatic plaque formation via IL-23-mediated activation of innate IL-17/IL-22-producing lymphocytes, independently of pDCs or IFN-I. These results suggest therapeutic targeting of IL-23 production by cDCs to refine current treatment strategies for psoriasis.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, 3015 GE, Rotterdam, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Wohn
authors.forename: Julia L
authors.initials: JL
authors.lastname: Ober-Blöbaum
authors.forename: Stefan
authors.initials: S
authors.lastname: Haak
authors.forename: Stanislav
authors.initials: S
authors.lastname: Pantelyushin
authors.forename: Cheolho
authors.initials: C
authors.lastname: Cheong
authors.forename: Sonja P
authors.initials: SP
authors.lastname: Zahner
authors.forename: Sabina
authors.initials: S
authors.lastname: Onderwater
authors.forename: Marius
authors.initials: M
authors.lastname: Kant
authors.forename: Heike
authors.initials: H
authors.lastname: Weighardt
authors.forename: Bernhard
authors.initials: B
authors.lastname: Holzmann
authors.forename: Boris
authors.initials: B
authors.lastname: Reizis
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.forename: Errol P
authors.initials: EP
authors.lastname: Prens
authors.forename: Björn E
authors.initials: BE
authors.lastname: Clausen
mesh_terms: D000634:Aminoquinolines / Q000008:administration & dosage; D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D000077271:Imiquimod; D053759:Interleukin-23 / Q000096:biosynthesis*; D007801:Langerhans Cells / Q000187:drug effects / Q000276:immunology*; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D037241:Mannose-Binding Lectins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000819:agonists; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D011565:Psoriasis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D051199:Toll-Like Receptor 7 / Q000819:agonists
chemical_list: D000634:Aminoquinolines; D000954:Antigens, Surface; C498497:Cd207 protein, mouse; D053759:Interleukin-23; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D000077271:Imiquimod