title: 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.
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.affiliation: 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.
authors.forename: Hongfei
authors.identifier: 0000-0002-8553-812X
authors.initials: H
authors.lastname: Lou
authors.affiliation: Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and.
authors.forename: Jingning
authors.initials: J
authors.lastname: Lu
authors.affiliation: Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and.
authors.forename: Eun Byul
authors.identifier: 0000-0001-7355-3405
authors.initials: EB
authors.lastname: Choi
authors.affiliation: Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and.
authors.forename: Min Hee
authors.initials: MH
authors.lastname: Oh
authors.affiliation: Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and.
authors.forename: Mingeum
authors.identifier: 0000-0002-7004-3853
authors.initials: M
authors.lastname: Jeong
authors.affiliation: Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and.
authors.forename: Sara
authors.identifier: 0000-0001-8188-9187
authors.initials: S
authors.lastname: Barmettler
authors.affiliation: Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and.
authors.forename: Zhou
authors.identifier: 0000-0002-1098-1135
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06510; and tao.zheng@yale.edu.
authors.forename: Tao
authors.identifier: 0000-0002-9410-688X
authors.initials: T
authors.lastname: Zheng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003876:Dermatitis, Atopic / Q000276:immunology*; D004195:Disease Models, Animal; D019886:Gastrin-Releasing Peptide / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007378:Interleukins / Q000276:immunology*; D015603:Keratinocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011537:Pruritus / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D019886:Gastrin-Releasing Peptide; D007378:Interleukins; D000097043:Interleukin-22