Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice.
Journal: 2013/November - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
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.
Relations:
Content
Citations
(87)
References
(33)
Diseases
(1)
Chemicals
(5)
Genes
(1)
Organisms
(3)
Processes
(2)
Anatomy
(1)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
Proc Natl Acad Sci U S A 110(34): 13921-13926

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

Supplementary Material

Supporting Information:
Departments of Dermatology and
Immunology and Medical Zoology and
Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya 663-8501, Japan; and
Department of Dermatology, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan
To whom correspondence may be addressed. E-mail: pj.ca.dem-oyh@nekakan or pj.ca.dem-oyh@sinamayk.
Edited* by Tadamitsu Kishimoto, Immunology Frontier Research Center, Osaka University, Suita, Japan, and approved July 18, 2013 (received for review April 24, 2013)

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.

Edited* by Tadamitsu Kishimoto, Immunology Frontier Research Center, Osaka University, Suita, Japan, and approved July 18, 2013 (received for review April 24, 2013)
Freely available online through the PNAS open access option.

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.

Keywords: Atopy, natural helper cells, nuocytes
Abstract

IL-33 is a member of the IL-1 family of cytokines and is a ligand for IL-1 receptor-like-1 or ST2 (1). In contrast with other members of that family, IL-1 and IL-18, which are activated in inflammasomes by caspase 1, IL-33 is produced in an active full-length form and is stored in the nucleus. In response to external insults or various types of cellular damage, IL-33 is released from cells and binds to ST2 on Th2 cells and on various types of innate immune cells including basophils, mast cells, eosinophils, and natural helper cells (2) or nuocytes (3), currently termed group 2 innate lymphoid cells (ILC2s) (4), which induces and activates those cells. IL-33 has been suggested to be involved in the pathogenesis of various allergic disorders such as asthma (5), allergic rhinitis (6), allergic conjunctivitis (7), and even rheumatoid arthritis (8) and inflammatory bowel diseases (9).

Atopic dermatitis (AD) is one of the major allergic disorders with a wide prevalence. Indeed, the morbidity of AD reaches 20–30% in developed countries (10). AD is characteristic of chronic dermatitis with severe, long-lasting itching, which often compromises the quality of life of patients and thereby influences social and economic activities. Clinically, eosinophils and mast cells accumulate in the lesional skin of patients with AD, often with an elevation of histamine and total IgE levels in peripheral blood (11). The association of AD with a polymorphism of the ST2 gene suggests that immune regulation via the IL-33-ST2 system may be pivotal as a genetic background of AD (12). Recently, the upregulation of IL-33 in the epidermis and the infiltration of ST2-positive cells in the dermis of the lesional skin of patients with AD have been reported (13, 14). In contrast, an increase in IL-33 has also been shown in the epidermis of patients with psoriasis, which is mediated mainly by Th1 and Th17 cells (1416). However, it is still unclear how IL-33 contributes to those inflammatory conditions involving skin in association with ILC2s, which produce massive amounts of Th2 cytokines in response to IL-33 (4).

In this study, we established transgenic mice with a skin-specific overexpression of IL-33. Interestingly, spontaneous dermatitis developed with the activation of ILC2s in those mice under specific pathogen-free (SPF) conditions, and the characteristics of those mice closely resemble atopic dermatitis.

Click here to view.

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.

Acknowledgments

Footnotes

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1307321110/-/DCSupplemental.

Footnotes

References

  • 1. Schmitz J, et al IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23(5):479–490.[PubMed][Google Scholar]
  • 2. Moro K, et al Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature. 2010;463(7280):540–544.[PubMed][Google Scholar]
  • 3. Neill DR, et al Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010;464(7293):1367–1370.[Google Scholar]
  • 4. Spits H, et al Innate lymphoid cells—a proposal for uniform nomenclature. Nat Rev Immunol. 2013;13(2):145–149.[PubMed][Google Scholar]
  • 5. Kondo Y, et al Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int Immunol. 2008;20(6):791–800.[PubMed][Google Scholar]
  • 6. Haenuki Y, et al. (2012) A critical role of IL-33 in experimental allergic rhinitis. J Allergy Clin Immunol 130(1):184–194.e111. [[PubMed]
  • 7. Matsuba-Kitamura S, et al Contribution of IL-33 to induction and augmentation of experimental allergic conjunctivitis. Int Immunol. 2010;22(6):479–489.[PubMed][Google Scholar]
  • 8. Matsuyama Y, et al Increased levels of interleukin 33 in sera and synovial fluid from patients with active rheumatoid arthritis. J Rheumatol. 2010;37(1):18–25.[PubMed][Google Scholar]
  • 9. Beltrán CJ, et al Characterization of the novel ST2/IL-33 system in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2010;16(7):1097–1107.[PubMed][Google Scholar]
  • 10. Schneider L, et al. (2013) Atopic dermatitis: A practice parameter update 2012. J Allergy Clin Immunol 131(2):295–299.e1-227. [[PubMed]
  • 11. Bieber TAtopic dermatitis. N Engl J Med. 2008;358(14):1483–1494.[PubMed][Google Scholar]
  • 12. Shimizu M, et al Functional SNPs in the distal promoter of the ST2 gene are associated with atopic dermatitis. Hum Mol Genet. 2005;14(19):2919–2927.[PubMed][Google Scholar]
  • 13. Savinko T, et al IL-33 and ST2 in atopic dermatitis: Expression profiles and modulation by triggering factors. J Invest Dermatol. 2012;132(5):1392–1400.[PubMed][Google Scholar]
  • 14. Meephansan J, Tsuda H, Komine M, Tominaga S, Ohtsuki MRegulation of IL-33 expression by IFN-γ and tumor necrosis factor-α in normal human epidermal keratinocytes. J Invest Dermatol. 2012;132(11):2593–2600.[PubMed][Google Scholar]
  • 15. Theoharides TC, et al IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc Natl Acad Sci USA. 2010;107(9):4448–4453.[Google Scholar]
  • 16. Hueber AJ, et al IL-33 induces skin inflammation with mast cell and neutrophil activation. Eur J Immunol. 2011;41(8):2229–2237.[PubMed][Google Scholar]
  • 17. Foster PS, et al Elemental signals regulating eosinophil accumulation in the lung. Immunol Rev. 2001;179:173–181.[PubMed][Google Scholar]
  • 18. Yamanaka K, et al Skin-specific caspase-1-transgenic mice show cutaneous apoptosis and pre-endotoxin shock condition with a high serum level of IL-18. J Immunol. 2000;165(2):997–1003.[PubMed][Google Scholar]
  • 19. Rankin AL, et al IL-33 induces IL-13-dependent cutaneous fibrosis. J Immunol. 2010;184(3):1526–1535.[PubMed][Google Scholar]
  • 20. Jin H, He R, Oyoshi M, Geha RSAnimal models of atopic dermatitis. J Invest Dermatol. 2009;129(1):31–40.[Google Scholar]
  • 21. Konishi H, et al IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions. Proc Natl Acad Sci USA. 2002;99(17):11340–11345.[Google Scholar]
  • 22. Kiehl P, Falkenberg K, Vogelbruch M, Kapp ATissue eosinophilia in acute and chronic atopic dermatitis: A morphometric approach using quantitative image analysis of immunostaining. Br J Dermatol. 2001;145(5):720–729.[PubMed][Google Scholar]
  • 23. Pushparaj PN, et al The cytokine interleukin-33 mediates anaphylactic shock. Proc Natl Acad Sci USA. 2009;106(24):9773–9778.[Google Scholar]
  • 24. Sakashita M, et al Association of serum interleukin-33 level and the interleukin-33 genetic variant with Japanese cedar pollinosis. Clin Exp Allergy. 2008;38(12):1875–1881.[PubMed][Google Scholar]
  • 25. Kim BS, et al. (2013) TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci Transl Med 5(170):170ra116.
  • 26. Monticelli LA, et al Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol. 2011;12(11):1045–1054.[Google Scholar]
  • 27. Yasuda K, et al Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice. Proc Natl Acad Sci USA. 2012;109(9):3451–3456.[Google Scholar]
  • 28. Mjösberg JM, et al Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol. 2011;12(11):1055–1062.[PubMed][Google Scholar]
  • 29. Corren JInhibition of interleukin-5 for the treatment of eosinophilic diseases. Discov Med. 2012;13(71):305–312.[PubMed][Google Scholar]
  • 30. Oldhoff JM, et al Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy. 2005;60(5):693–696.[PubMed][Google Scholar]
  • 31. Haldar P, et al Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360(10):973–984.[Google Scholar]
  • 32. Guttman-Yassky E, Nograles KE, Krueger JGContrasting pathogenesis of atopic dermatitis and psoriasis—part II: Immune cell subsets and therapeutic concepts. J Allergy Clin Immunol. 2011;127(6):1420–1432.[PubMed][Google Scholar]
  • 33. Imai Y, et al Freshly isolated Langerhans cells negatively regulate naïve T cell activation in response to peptide antigen through cell-to-cell contact. J Dermatol Sci. 2008;51(1):19–29.[PubMed][Google Scholar]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.