title: IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A.
abstract: IL-23 and Th17 cells producing IL-17A and IL-22 are found in excess in skin affected by psoriasis. Previous studies showed that IL-22, but not IL-17A, mediates psoriasis-like epidermal hyperplasia following recombinant murine (rm)IL-23 injections into skin. To further investigate the role of IL-17A, ears of mice were injected with rmIL-23. Investigators blinded to treatment conditions and mouse genotypes measured ear swelling, epidermal thickness, and cytokine expression. In wild-type (WT) mice, rmIL-23 induced ear swelling (p < 0.001, all p values versus saline), epidermal hyperplasia by histology (p < 0.001) and confocal microscopy (p < 0.004), and expression of both IL-17A and IL-22. As expected, rmIL-23 injections into IL-22(-/-) mice resulted in relatively little ear swelling (p < 0.09) and epidermal hyperplasia (p < 0.51 by histology and p < 0.75 by confocal microscopy). Notably, rmIL-23 injections into IL-17A(-/-) mice produced little ear swelling (p < 0.001, versus IL-23-injected WT mice) and epidermal hyperplasia (p < 0.001 by histology and p < 0.005 by confocal microscopy), even though IL-22 was readily induced in these mice. Furthermore, systemic delivery of blocking Abs directed against either IL-22 or IL-17A completely inhibited IL-23-induced epidermal hyperplasia in WT mice. These results demonstrate that IL-17A, like IL-22, is a downstream mediator for IL-23-induced changes in murine skin and that both of these Th17 cytokines are necessary to produce IL-23-mediated skin pathology. IL-17A may represent an attractive therapeutic target in individuals with psoriasis by blocking downstream effects of IL-23.
authors.affiliation: Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Rizzo
authors.forename: Shinji
authors.initials: S
authors.lastname: Kagami
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Phillips
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Kurtz
authors.forename: Steven L
authors.initials: SL
authors.lastname: Jacques
authors.forename: Andrew
authors.initials: A
authors.lastname: Blauvelt
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D004817:Epidermis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D006965:Hyperplasia; D007271:Injections, Intradermal; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D053759:Interleukin-23 / Q000008:administration & dosage / Q000502:physiology*; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011565:Psoriasis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D000097043:Interleukin-22
chemical_list: D019138:Antibodies, Blocking; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D000097043:Interleukin-22