IL-25 enhances TH17 cell-mediated contact dermatitis by promoting IL-1β production by dermal dendritic cells

Hajime Suto; Aya Nambu; Hideaki Morita; Sachiko Yamaguchi; Takafumi Numata; Takamichi Yoshizaki; Eri Shimura; Ken Arae; Yousuke Asada; Kenichiro Motomura; Mari Kaneko; Takaya Abe; Akira Matsuda; Yoichiro Iwakura; Ko Okumura; Hirohisa Saito; Kenji Matsumoto; Katsuko Sudo; Susumu Nakae

doi:10.1016/j.jaci.2017.12.1007

IL-25 enhances T_H17 cell-mediated contact dermatitis by promoting IL-1β production by dermal dendritic cells

J Allergy Clin Immunol. 2018 Nov;142(5):1500-1509.e10. doi: 10.1016/j.jaci.2017.12.1007. Epub 2018 Mar 6.

Authors

Hajime Suto¹, Aya Nambu², Hideaki Morita³, Sachiko Yamaguchi², Takafumi Numata², Takamichi Yoshizaki², Eri Shimura⁴, Ken Arae⁵, Yousuke Asada⁶, Kenichiro Motomura³, Mari Kaneko⁷, Takaya Abe⁸, Akira Matsuda⁶, Yoichiro Iwakura⁹, Ko Okumura¹, Hirohisa Saito³, Kenji Matsumoto³, Katsuko Sudo¹⁰, Susumu Nakae¹¹

Affiliations

¹ Atopy Research Center, Juntendo University, Tokyo, Japan.
² Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
³ Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
⁴ Atopy Research Center, Juntendo University, Tokyo, Japan; Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
⁵ Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Immunology, Faculty of Health Science, Kyorin University, Tokyo, Japan.
⁶ Department of Ophthalmology, Juntendo University, Tokyo, Japan.
⁷ Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe, Japan; Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan.
⁸ Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan.
⁹ Center for Experimental Animal Models, Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan.
¹⁰ Animal Research Center, Tokyo Medical University, Tokyo, Japan.
¹¹ Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan. Electronic address: snakae@ims.u-tokyo.ac.jp.

PMID: 29522843
DOI: 10.1016/j.jaci.2017.12.1007

Abstract

Background: In addition to thymic stromal lymphopoietin and IL-33, IL-25 is known to induce T_H2 cytokine production by various cell types, including T_H2 cells, T_H9 cells, invariant natural killer T cells, and group 2 innate lymphoid cells, involved in T_H2-type immune responses. Because both T_H2-type and T_H17-type cells/cytokines are crucial for contact hypersensitivity (CHS), IL-25 can contribute to this by enhancing T_H2-type immune responses. However, the precise role of IL-25 in the pathogenesis of fluorescein isothiocyanate-induced CHS is poorly understood.

Objective: We investigated the contribution of IL-25 to CHS using Il25^-/- mice.

Methods: CHS was evaluated by means of measurement of ear skin thickness in mice after fluorescein isothiocyanate painting. Skin dendritic cell (DC) migration, hapten-specific T_H cell differentiation, and detection of IL-1β-producing cells were determined by using flow cytometry, ELISA, and immunohistochemistry, respectively.

Results: In contrast to thymic stromal lymphopoietin, we found that IL-25 was not essential for skin DC migration or hapten-specific T_H cell differentiation in the sensitization phase of CHS. Unexpectedly, mast cell- and non-immune cell-derived IL-25 was important for hapten-specific T_H17 cell-mediated rather than T_H2 cell-mediated inflammation in the elicitation phase of CHS by enhancing T_H17-related, but not T_H2-related, cytokines in the skin. In particular, IL-1β produced by dermal DCs in response to IL-25 was crucial for hapten-specific T_H17 cell activation, contributing to induction of local inflammation in the elicitation phase of CHS.

Conclusion: Our results identify a novel IL-25 inflammatory pathway involved in induction of T_H17 cell-mediated, but not T_H2 cell-mediated, CHS. IL-25 neutralization can be a potential approach for treatment of CHS.

Keywords: IL-25; IL-33; T(H)17; T(H)2; contact hypersensitivity; gene-deficient mice; thymic stromal lymphopoietin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cytokines / genetics
Cytokines / immunology*
DNA-Binding Proteins / genetics
Dermatitis, Allergic Contact / immunology*
Female
Male
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
STAT6 Transcription Factor / genetics
Th17 Cells / immunology*
Thymic Stromal Lymphopoietin

Substances

Cytokines
DNA-Binding Proteins
Nuclear Receptor Subfamily 1, Group F, Member 3
Rag2 protein, mouse
Rorc protein, mouse
STAT6 Transcription Factor
Stat6 protein, mouse
Thymic Stromal Lymphopoietin
TSLP protein, mouse