IL-17 Receptor A Maintains and Protects the Skin Barrier To Prevent Allergic Skin Inflammation.

Abstract

Atopic dermatitis (AD) is a common inflammatory skin disease affecting up to 20% of children and 3% of adults worldwide and is associated with dysregulation of the skin barrier. Although type 2 responses are implicated in AD, emerging evidence indicates a potential role for the IL-17A signaling axis in AD pathogenesis. In this study we show that in the filaggrin mutant mouse model of spontaneous AD, IL-17RA deficiency (Il17ra-/- ) resulted in severe exacerbation of skin inflammation. Interestingly, Il17ra-/- mice without the filaggrin mutation also developed spontaneous progressive skin inflammation with eosinophilia, as well as increased levels of thymic stromal lymphopoietin (TSLP) and IL-5 in the skin. Il17ra-/- mice have a defective skin barrier with altered filaggrin expression. The barrier dysregulation and spontaneous skin inflammation in Il17ra-/- mice was dependent on TSLP, but not the other alarmins IL-25 and IL-33. The associated skin inflammation was mediated by IL-5-expressing pathogenic effector Th2 cells and was independent of TCRγδ T cells and IL-22. An absence of IL-17RA in nonhematopoietic cells, but not in the hematopoietic cells, was required for the development of spontaneous skin inflammation. Skin microbiome dysbiosis developed in the absence of IL-17RA, with antibiotic intervention resulting in significant amelioration of skin inflammation and reductions in skin-infiltrating pathogenic effector Th2 cells and TSLP. This study describes a previously unappreciated protective role for IL-17RA signaling in regulation of the skin barrier and maintenance of skin immune homeostasis.

• Authors: Achilleas Floudas, Sean P Saunders, Tara Moran, Christian Schwartz, Emily Hams, Denise C Fitzgerald, James A Johnston, Graham S Ogg, Andrew N McKenzie, Patrick T Walsh, Padraic G Fallon
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 199 Issue 2 Pg. 707-717 (07 15 2017) ISSN: 1550-6606 [Electronic] United States
• PMID: 28615416 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 by The American Association of Immunologists, Inc.

Chemical References

• Cytokines
• FLG protein, human
• Filaggrin Proteins
• Il17ra protein, mouse
• Il33 protein, mouse
• Interleukin-33
• Interleukin-5
• Interleukins
• Intermediate Filament Proteins
• Mydgf protein, mouse
• Receptors, Antigen, T-Cell, gamma-delta
• Receptors, Interleukin-17
• interleukin-22
• Thymic Stromal Lymphopoietin
• TSLP protein, mouse

Topics

• Animals
• Cytokines (immunology)
• Dermatitis, Atopic (immunology, pathology)
• Disease Models, Animal
• Dysbiosis
• Eosinophilia (immunology)
• Filaggrin Proteins
• Gene Expression Regulation
• Homeostasis
• Interleukin-33 (immunology)
• Interleukin-5 (genetics, immunology)
• Interleukins (genetics, immunology)
• Intermediate Filament Proteins (deficiency, genetics)
• Mice
• Microbiota
• Mutation
• Receptors, Antigen, T-Cell, gamma-delta (immunology)
• Receptors, Interleukin-17 (deficiency, genetics, immunology, metabolism)
• Signal Transduction
• Skin (growth & development, immunology, microbiology, pathology)
• Th2 Cells (immunology)
• Thymic Stromal Lymphopoietin