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. 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.
Abstract
BACKGROUND: In addition to thymic stromal lymphopoietin and IL-33, IL-25 is known to induce TH2 cytokine production by various cell types, including TH2 cells, TH9 cells, invariant natural killer T cells, and group 2 innate lymphoid cells, involved in TH2-type immune responses. Because both TH2-type and TH17-type cells/cytokines are crucial for contact hypersensitivity (CHS), IL-25 can contribute to this by enhancing TH2-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 TH 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 TH cell differentiation in the sensitization phase of CHS. Unexpectedly, mast cell- and non-immune cell-derived IL-25 was important for hapten-specific TH17 cell-mediated rather than TH2 cell-mediated inflammation in the elicitation phase of CHS by enhancing TH17-related, but not TH2-related, cytokines in the skin. In particular, IL-1β produced by dermal DCs in response to IL-25 was crucial for hapten-specific TH17 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 TH17 cell-mediated, but not TH2 cell-mediated, CHS. IL-25 neutralization can be a potential approach for treatment of CHS.
BACKGROUND: In addition to thymic stromal lymphopoietin and IL-33, IL-25 is known to induce TH2 cytokine production by various cell types, including TH2 cells, TH9 cells, invariant natural killer T cells, and group 2 innate lymphoid cells, involved in TH2-type immune responses. Because both TH2-type and TH17-type cells/cytokines are crucial for contact hypersensitivity (CHS), IL-25 can contribute to this by enhancing TH2-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 TH 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 TH cell differentiation in the sensitization phase of CHS. Unexpectedly, mast cell- and non-immune cell-derived IL-25 was important for hapten-specific TH17 cell-mediated rather than TH2 cell-mediated inflammation in the elicitation phase of CHS by enhancing TH17-related, but not TH2-related, cytokines in the skin. In particular, IL-1β produced by dermal DCs in response to IL-25 was crucial for hapten-specific TH17 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 TH17 cell-mediated, but not TH2 cell-mediated, CHS. IL-25 neutralization can be a potential approach for treatment of CHS.