title: EGFR signaling blunts allergen-induced IL-6 production and Th17 responses in the skin and attenuates development and relapse of atopic dermatitis.
abstract: Despite the important role for epidermal growth factor (EGF) in epithelial homeostasis and wound healing, it has not been investigated in atopic dermatitis (AD). We used AD animal models to explore the role of EGF in AD. In an acute AD model, skin transepidermal water loss was significantly attenuated in EGF-treated mice. Blockade of EGFR signaling genetically or pharmacologically confirms a protective role for EGFR signaling in AD. In a chronic/relapsing AD model, EGF treatment of mice with established AD resulted in an attenuation of AD exacerbation (skin epithelial thickness, cutaneous inflammation, and total and allergen specific IgE) following cutaneous allergen rechallenge. EGF treatment did not alter expression of skin barrier junction proteins or antimicrobial peptides in the AD model. However, EGF treatment attenuated allergen-induced expression of IL-17A, CXCL1, and CXCL2 and neutrophil accumulation in AD skin following cutaneous allergen exposure. IL-17A production was decreased in the in vitro restimulated skin-draining lymph node cells from the EGF-treated mice. Similarly, IL-17A was increased in waved-2 mice skin following allergen exposure. Whereas IL-6 and IL-1β expression was attenuated in the skin of EGF-treated mice, EGF treatment also suppressed allergen-induced IL-6 production by keratinocytes. Given the central role of IL-6 in priming Th17 differentiation in the skin, this effect of EGF on keratinocytes may contribute to the protective roles for EGFR in AD pathogenesis. In conclusion, our study provides evidence for a previously unrecognized protective role for EGF in AD and a new role for EGF in modulating IL-17 responses in the skin.
authors: Division of Asthma Research, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors: Zhonghua
authors: Z
authors: Zhang
authors: Chang
authors: C
authors: Xiao
authors: Aaron M
authors: AM
authors: Gibson
authors: Stacey A
authors: SA
authors: Bass
authors: Gurjit K
authors: GK
authors: Khurana Hershey
mesh_terms: D000279:Administration, Cutaneous; D000485:Allergens / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000096:biosynthesis / Q000235:genetics; D054426:Chemokine CXCL2 / Q000096:biosynthesis / Q000235:genetics; D003876:Dermatitis, Atopic / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology*; D000069347:Erlotinib Hydrochloride; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011799:Quinazolines / Q000494:pharmacology; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D012867:Skin / Q000276:immunology* / Q000473:pathology; D013047:Specific Pathogen-Free Organisms; D058504:Th17 Cells / Q000276:immunology*; D000097043:Interleukin-22
chemical_list: D000485:Allergens; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D007378:Interleukins; D011799:Quinazolines; D000097043:Interleukin-22; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C098680:Il17a protein, mouse; C577686:interleukin-6, mouse; C541485:EGFR protein, mouse