Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice

Edited by Tadamitsu Kishimoto, Immunology Frontier Research Center, Osaka University, Suita, Japan, and approved July 18, 2013 (received for review April 24, 2013)
August 5, 2013
110 (34) 13921-13926

Abstract

Transgenic mice expressing the mouse interleukin 33 (IL-33) gene driven by a keratin 14 promoter were generated. The skin-selective expression of the IL-33 gene was enhanced, and intense immunofluorescence for IL-33 was evident in the nuclei of the epidermis. Spontaneous itchy dermatitis developed in those mice at 6–8 wk of age in specific pathogen-free conditions. In the lesional skin, the epidermis was thickened and the eosinophils were infiltrated with increased expression of the eosinophil peroxidase and major basic protein genes. Mast cells were also abundant there, and blood histamine and total IgE levels were high. Those phenotypes closely resemble the features of atopic dermatitis. In peripheral blood and lesional skin, IL-5, IL-13, regulated upon activation, normally T-expressed, and presumably secreted (RANTES)/CCL5, and Eotaxin 1/CCL11 were increased, whereas TNF-α, IFN-γ, and thymic stromal lymphopoietin (TSLP) were unaltered. Furthermore, the proportion of group 2 innate lymphoid cells (ILC2s), which produce IL-5, were significantly increased in the lesional skin, peripheral blood, and regional lymph nodes. The dermatitis with eosinophil infiltration was improved by the administration of an anti-IL-5 antibody. These results suggest that the expression of IL-33 in the skin activates an immune response involving ILC2 and that this process might play a crucial role in the pathogenesis of allergic inflammation that is characteristic of atopic dermatitis.

Acknowledgments

We thank Dr. Naoki Takeda and members of the Center for Animal Resources and Development, Kumamoto University, and members of the Institute of Experimental Animal Sciences and the Joint-Use Research Facilities, Hyogo College of Medicine, for their technical assistance. This work was supported in part by Ministry of Education, Culture, Sports, Science and Technology (MEXT) or Japan Society for the Promotion of Science (JSPS) KAKENHI (22791093, 23791297, 23249022, and 24791183) and by a Strategic Program Grant for Research Institute Development in Private Institute from MEXT in Japan, by a grant from the “Research on Measures for Intractable Diseases” Project, matching fund subsidy (H23-028), and by a Health and Labour Sciences Research Grant Adjuvant Database Project from the Ministry of Health, Labour, and Welfare, Japan.

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 110 | No. 34
August 20, 2013
PubMed: 23918359

Classifications

Submission history

Published online: August 5, 2013
Published in issue: August 20, 2013

Keywords

  1. Atopy
  2. natural helper cells
  3. nuocytes

Acknowledgments

We thank Dr. Naoki Takeda and members of the Center for Animal Resources and Development, Kumamoto University, and members of the Institute of Experimental Animal Sciences and the Joint-Use Research Facilities, Hyogo College of Medicine, for their technical assistance. This work was supported in part by Ministry of Education, Culture, Sports, Science and Technology (MEXT) or Japan Society for the Promotion of Science (JSPS) KAKENHI (22791093, 23791297, 23249022, and 24791183) and by a Strategic Program Grant for Research Institute Development in Private Institute from MEXT in Japan, by a grant from the “Research on Measures for Intractable Diseases” Project, matching fund subsidy (H23-028), and by a Health and Labour Sciences Research Grant Adjuvant Database Project from the Ministry of Health, Labour, and Welfare, Japan.

Notes

*This Direct Submission article had a prearranged editor.

Authors

Affiliations

Yasutomo Imai
Departments of aDermatology and
Koubun Yasuda
Immunology and Medical Zoology and
Yoshiko Sakaguchi
Departments of aDermatology and
Takashi Haneda
Departments of aDermatology and
Hitoshi Mizutani
Department of Dermatology, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan
Tomohiro Yoshimoto
Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya 663-8501, Japan; and
Kenji Nakanishi1 [email protected]
Immunology and Medical Zoology and
Kiyofumi Yamanishi1 [email protected]
Departments of aDermatology and

Notes

1
To whom correspondence may be addressed. E-mail: [email protected] or [email protected].
Author contributions: Y.I., K. Yasuda, T.H., H.M., T.Y., K.N., and K. Yamanishi designed research; Y.I., K. Yasuda, Y.S., and K. Yamanishi performed research; Y.I., K. Yasuda, T.H., H.M., T.Y., K.N., and K. Yamanishi analyzed data; Y.I., K. Yasuda, K.N., and K. Yamanishi wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice
    Proceedings of the National Academy of Sciences
    • Vol. 110
    • No. 34
    • pp. 13693-14030

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