title: IL-23 induced in keratinocytes by endogenous TLR4 ligands polarizes dendritic cells to drive IL-22 responses to skin immunization.
abstract: Atopic dermatitis (AD) is a Th2-dominated inflammatory skin disease characterized by epidermal thickening. Serum levels of IL-22, a cytokine known to induce keratinocyte proliferation, are elevated in AD, and Th22 cells infiltrate AD skin lesions. We show that application of antigen to mouse skin subjected to tape stripping, a surrogate for scratching, induces an IL-22 response that drives epidermal hyperplasia and keratinocyte proliferation in a mouse model of skin inflammation that shares many features of AD. DC-derived IL-23 is known to act on CD4(+) T cells to induce IL-22 production. However, the mechanisms that drive IL-23 production by skin DCs in response to cutaneous sensitization are not well understood. We demonstrate that IL-23 released by keratinocytes in response to endogenous TLR4 ligands causes skin DCs, which selectively express IL-23R, to up-regulate their endogenous IL-23 production and drive an IL-22 response in naive CD4(+) T cells that mediates epidermal thickening. We also show that IL-23 is released in human skin after scratching and polarizes human skin DCs to drive an IL-22 response, supporting the utility of IL-23 and IL-22 blockade in AD.
authors.affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Juhan
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Juan Manuel
authors.identifier: 0000-0001-7394-4457
authors.initials: JM
authors.lastname: Leyva-Castillo
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
authors.forename: Guoxing
authors.identifier: 0000-0001-7762-4848
authors.initials: G
authors.lastname: Wang
authors.affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Claire
authors.identifier: 0000-0001-8005-4831
authors.initials: C
authors.lastname: Galand
authors.affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Michiko K
authors.initials: MK
authors.lastname: Oyoshi
authors.affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Lalit
authors.identifier: 0000-0003-2045-298X
authors.initials: L
authors.lastname: Kumar
authors.affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hoff
authors.affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Rui
authors.identifier: 0000-0001-5288-9786
authors.initials: R
authors.lastname: He
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637.
authors.forename: Alexander
authors.initials: A
authors.lastname: Chervonsky
authors.affiliation: Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, MD 21702.
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
authors.affiliation: Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Vijay K
authors.identifier: 0000-0001-7177-2110
authors.initials: VK
authors.lastname: Kuchroo
authors.affiliation: Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Marcel R M
authors.identifier: 0000-0003-0696-4401
authors.initials: MR
authors.lastname: van den Brink
authors.affiliation: Merck Research Laboratories, Palo Alto, CA 94304.
authors.forename: Rene De Waal
authors.identifier: 0000-0002-2663-383X
authors.initials: Rde W
authors.lastname: Malefyt
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université Laval, Sainte-Foy, Quebec QC G1V 4G2, Canada.
authors.forename: Philippe A
authors.identifier: 0000-0001-7177-7763
authors.initials: PA
authors.lastname: Tessier
authors.affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Robert
authors.identifier: 0000-0002-0911-9310
authors.initials: R
authors.lastname: Fuhlbrigge
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
authors.forename: Cox
authors.identifier: 0000-0001-6233-7029
authors.initials: C
authors.lastname: Terhorst
authors.affiliation: Department of Dermatology, Harvard Medical School, Boston, MA 02115 Division of Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: George
authors.identifier: 0000-0002-3909-1160
authors.initials: G
authors.lastname: Murphy
authors.affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115 raif.geha@childrens.harvard.edu.
authors.forename: Raif S
authors.identifier: 0000-0002-6019-3751
authors.initials: RS
authors.lastname: Geha
mesh_terms: D000328:Adult; D000818:Animals; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D004817:Epidermis / Q000473:pathology; D005260:Female; D006410:Hematopoiesis; D006801:Humans; D007114:Immunization; D053759:Interleukin-23 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism*; D008024:Ligands; D008198:Lymph Nodes / Q000378:metabolism; D008807:Mice, Inbred BALB C; D012867:Skin / Q000276:immunology* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D000097043:Interleukin-22
chemical_list: D000941:Antigens; D053759:Interleukin-23; D007378:Interleukins; D008024:Ligands; D051197:Toll-Like Receptor 4; D000097043:Interleukin-22