Ana P M Serezani1, Gunseli Bozdogan1, Sarita Sehra1, Daniel Walsh1, Purna Krishnamurthy1, Elizabeth A Sierra Potchanant2, Grzegorz Nalepa2, Shreevrat Goenka1, Matthew J Turner3, Dan F Spandau3, Mark H Kaplan4. 1. Department of Pediatrics, H.B. Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Ind. 2. Department of Pediatrics, H.B. Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Ind; Division of Pediatric Hematology-Oncology Bone Marrow Failure Program, Indiana University School of Medicine, Indianapolis, Ind; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Ind. 3. Department of Dermatology, Indiana University School of Medicine, Indianapolis, Ind. 4. Department of Pediatrics, H.B. Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Ind. Electronic address: mkaplan2@iupui.edu.
Abstract
BACKGROUND: Atopic dermatitis (AD) is characterized by intense pruritis and is a common childhood inflammatory disease. Many factors are known to affect AD development, including the pleiotropic cytokine IL-4. Yet little is known regarding the direct effects of IL-4 on keratinocyte function. OBJECTIVE AND METHODS: In this report RNA sequencing and functional assays were used to define the effect of the allergic environment on primary keratinocyte function and wound repair in mice. RESULTS: Acute or chronic stimulation by IL-4 modified expression of more than 1000 genes expressed in human keratinocytes that are involved in a broad spectrum of nonoverlapping functions. Among the IL-4-induced changes, repression of fibronectin critically impaired the human keratinocyte wound response. Moreover, in mouse models of spontaneous and induced AD-like lesions, there was delayed re-epithelialization. Importantly, topical treatment with fibronectin restored the epidermal repair response. CONCLUSION: Keratinocyte gene expression is critically shaped by IL-4, altering cell fate decisions, which are likely important for the clinical manifestations and pathology of allergic skin disease.
BACKGROUND:Atopic dermatitis (AD) is characterized by intense pruritis and is a common childhood inflammatory disease. Many factors are known to affect AD development, including the pleiotropic cytokine IL-4. Yet little is known regarding the direct effects of IL-4 on keratinocyte function. OBJECTIVE AND METHODS: In this report RNA sequencing and functional assays were used to define the effect of the allergic environment on primary keratinocyte function and wound repair in mice. RESULTS: Acute or chronic stimulation by IL-4 modified expression of more than 1000 genes expressed in human keratinocytes that are involved in a broad spectrum of nonoverlapping functions. Among the IL-4-induced changes, repression of fibronectin critically impaired the human keratinocyte wound response. Moreover, in mouse models of spontaneous and induced AD-like lesions, there was delayed re-epithelialization. Importantly, topical treatment with fibronectin restored the epidermal repair response. CONCLUSION: Keratinocyte gene expression is critically shaped by IL-4, altering cell fate decisions, which are likely important for the clinical manifestations and pathology of allergic skin disease.
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