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Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus via Stimulating Epithelial Th2 Cytokines and the GRP Pathway.
J Immunol 2017; 198(7):2543-2555JI

Abstract

Increased expression of Th22 cytokine IL-22 is a characteristic finding in atopic dermatitis (AD). However, the specific role of IL-22 in the pathogenesis of AD in vivo has yet to be elucidated. Consistent with observations in human AD, IL-22 was significantly increased in the AD skin of mice after epicutaneous sensitization to house dust mite allergen. Utilizing a skin-specific inducible transgenic system, we show in the present study that expression of IL-22 in the skin of mice caused an AD-like phenotype characterized by chronic pruritic dermatitis associated with Th2-biased local and systemic immune responses, downregulation of epidermal differentiation complex genes, and enhanced dermatitis upon epicutaneous allergen exposure. IL-22 potently induced the expression of gastrin-releasing peptide (GRP), a neuropeptide pruritogen, in dermal immune cells and sensory afferents and in their skin-innervating sensory neurons. IL-22 also differentially upregulated the expression of GRP receptor (GRPR) on keratinocytes of AD skin. The number of GRP+ cells in the skin correlated with the AD severity and the intensity of pruritus. IL-22 directly upregulated the expression of epithelial-derived type 2 cytokines (thymic stromal lymphopoietin and IL-33) and GRP in primary keratinocytes. Furthermore, GRP not only strongly induced thymic stromal lymphopoietin but it also increased the expression of IL-33 and GRPR synergistically with IL-22. Importantly, we found that the expression of GRP was strikingly increased in the skin of patients with AD. These results indicate that IL-22 plays important pathogenic roles in the initiation and development of AD, in part through inducing keratinocyte production of type 2 cytokines and activation of the GRP/GRPR pathway.

Authors+Show Affiliations

Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and. Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, People's Republic of China.Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and.Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and.Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and.Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and.Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and.Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and.Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and tao.zheng@yale.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28228560

Citation

Lou, Hongfei, et al. "Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus Via Stimulating Epithelial Th2 Cytokines and the GRP Pathway." Journal of Immunology (Baltimore, Md. : 1950), vol. 198, no. 7, 2017, pp. 2543-2555.
Lou H, Lu J, Choi EB, et al. Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus via Stimulating Epithelial Th2 Cytokines and the GRP Pathway. J Immunol. 2017;198(7):2543-2555.
Lou, H., Lu, J., Choi, E. B., Oh, M. H., Jeong, M., Barmettler, S., ... Zheng, T. (2017). Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus via Stimulating Epithelial Th2 Cytokines and the GRP Pathway. Journal of Immunology (Baltimore, Md. : 1950), 198(7), pp. 2543-2555. doi:10.4049/jimmunol.1600126.
Lou H, et al. Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus Via Stimulating Epithelial Th2 Cytokines and the GRP Pathway. J Immunol. 2017 04 1;198(7):2543-2555. PubMed PMID: 28228560.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus via Stimulating Epithelial Th2 Cytokines and the GRP Pathway. AU - Lou,Hongfei, AU - Lu,Jingning, AU - Choi,Eun Byul, AU - Oh,Min Hee, AU - Jeong,Mingeum, AU - Barmettler,Sara, AU - Zhu,Zhou, AU - Zheng,Tao, Y1 - 2017/02/22/ PY - 2016/01/21/received PY - 2017/01/28/accepted PY - 2017/2/24/pubmed PY - 2017/8/16/medline PY - 2017/2/24/entrez SP - 2543 EP - 2555 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 198 IS - 7 N2 - Increased expression of Th22 cytokine IL-22 is a characteristic finding in atopic dermatitis (AD). However, the specific role of IL-22 in the pathogenesis of AD in vivo has yet to be elucidated. Consistent with observations in human AD, IL-22 was significantly increased in the AD skin of mice after epicutaneous sensitization to house dust mite allergen. Utilizing a skin-specific inducible transgenic system, we show in the present study that expression of IL-22 in the skin of mice caused an AD-like phenotype characterized by chronic pruritic dermatitis associated with Th2-biased local and systemic immune responses, downregulation of epidermal differentiation complex genes, and enhanced dermatitis upon epicutaneous allergen exposure. IL-22 potently induced the expression of gastrin-releasing peptide (GRP), a neuropeptide pruritogen, in dermal immune cells and sensory afferents and in their skin-innervating sensory neurons. IL-22 also differentially upregulated the expression of GRP receptor (GRPR) on keratinocytes of AD skin. The number of GRP+ cells in the skin correlated with the AD severity and the intensity of pruritus. IL-22 directly upregulated the expression of epithelial-derived type 2 cytokines (thymic stromal lymphopoietin and IL-33) and GRP in primary keratinocytes. Furthermore, GRP not only strongly induced thymic stromal lymphopoietin but it also increased the expression of IL-33 and GRPR synergistically with IL-22. Importantly, we found that the expression of GRP was strikingly increased in the skin of patients with AD. These results indicate that IL-22 plays important pathogenic roles in the initiation and development of AD, in part through inducing keratinocyte production of type 2 cytokines and activation of the GRP/GRPR pathway. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/28228560/Expression_of_IL_22_in_the_Skin_Causes_Th2_Biased_Immunity_Epidermal_Barrier_Dysfunction_and_Pruritus_via_Stimulating_Epithelial_Th2_Cytokines_and_the_GRP_Pathway_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=28228560 DB - PRIME DP - Unbound Medicine ER -