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Harvard Medical School

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J. Exp. Med., Published August 22, 2016 | doi: 10.1084/jem.20150376 IL-23 induced in keratinocytes by endogenous TLR4 ligands polarizes dendritic cells to drive IL-22 responses to skin immunization

Abstract

Juhan Yoon,^1,* Juan Manuel Leyva-Castillo,^1,* Guoxing Wang,² Claire Galand,¹ Michiko K. Oyoshi,¹ Lalit Kumar,¹ Sabine Hoff,¹ Rui He,¹ Alexander Chervonsky,⁶ Joost J. Oppenheim,⁷ Vijay K. Kuchroo,⁴ Marcel R.M. van den Brink,⁸ Rene De Waal Malefyt,⁹ Philippe A. Tessier,¹⁰ Robert Fuhlbrigge,¹ Philip Rosenstiel,¹¹ Cox Terhorst,² George Murphy,^3,5 and Raif S. Geha¹¹Division of Immunology, Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115
²Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115
³Department of Dermatology, Harvard Medical School, Boston, MA 02115
⁴Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
⁵Division of Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
⁶Department of Pathology, University of Chicago, Chicago, IL 60637
⁷Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, MD 21702
⁸Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
⁹Merck Research Laboratories, Palo Alto, CA 94304
¹⁰Centre de Recherche du Centre Hospitalier de l’Universite Laval, Sainte-Foy, Quebec QC G1V 4G2, Canada
¹¹Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany

^* J. Yoon and J.M. Leyva-Castillo contributed equally to this paper.

J. Yoon’s present address is C&C Research Laboratories, DRC, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do 440-746, South Korea.
S. Hoff’s present address is Dept. of Immunotherapy and Antibody Drug Conjugates, Bayer Pharma AG, 13353 Berlin, Germany.
R. He’s present address is Dept. of Immunology, Shanghai Medical College, Fudan University, Shanghai 200030, China.

Correspondence to Raif S. Geha

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.

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형식Research article
게재일2016년 08월 (BRIC 등록일 2016-08-25)
연구진국외 연구진
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