title: Counterregulation between thymic stromal lymphopoietin- and IL-23-driven immune axes shapes skin inflammation in mice with epidermal barrier defects.
abstract: Epidermal barrier dysfunction has been recognized as a critical factor in the initiation and exacerbation of skin inflammation, particularly in patients with atopic dermatitis (AD) and AD-like congenital disorders, including peeling skin syndrome type B. However, inflammatory responses developed in barrier-defective skin, as well as the underlying mechanisms, remained incompletely understood.
  
  
  
  We aimed to decipher inflammatory axes and the cytokine network in mouse skin on breakdown of epidermal stratum corneum barrier.
  
  
  
  We generated Cdsn(iep-/-) mice with corneodesmosin ablation in keratinocytes selectively in an inducible manner. We characterized inflammatory responses and cytokine expression by using histology, immunohistochemistry, ELISA, and quantitative PCR. We combined mouse genetic tools, antibody-mediated neutralization, signal-blocking reagents, and topical antibiotic treatment to explore the inflammatory axes.
  
  
  
  We show that on breakdown of the epidermal stratum corneum barrier, type 2 and type 17 inflammatory responses are developed simultaneously, driven by thymic stromal lymphopoietin (TSLP) and IL-23, respectively. Importantly, we reveal a counterregulation between these 2 inflammatory axes. Furthermore, we show that protease-activated receptor 2 signaling is involved in mediating the TSLP/type 2 axis, whereas skin bacteria are engaged in induction of the IL-23/type 17 axis. Moreover, we find that IL-1β is induced in skin of Cdsn(iep-/-) mice and that blockade of IL-1 signaling suppresses both TSLP and IL-23 expression and ameliorates skin inflammation.
  
  
  
  The inflammatory phenotype in barrier-defective skin is shaped by counterregulation between the TSLP/type 2 and IL-23/type 17 axes. Targeting IL-1 signaling could be a promising therapeutic option for controlling skin inflammation in patients with peeling skin syndrome type B and other diseases related to epidermal barrier dysfunction, including AD.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR7104/Institut National de la Santé et de la Recherche Médicale U964/Université de Strasbourg, Illkirch, France.
authors.forename: Jiagui
authors.initials: J
authors.lastname: Li
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR7104/Institut National de la Santé et de la Recherche Médicale U964/Université de Strasbourg, Illkirch, France.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Leyva-Castillo
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR7104/Institut National de la Santé et de la Recherche Médicale U964/Université de Strasbourg, Illkirch, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hener
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR7104/Institut National de la Santé et de la Recherche Médicale U964/Université de Strasbourg, Illkirch, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Eisenmann
authors.affiliation: Différenciation Epidermique et Autoimmunité Rhumatoïde, Centre National de la Recherche Scientifique UMR5165/Institut National de la Recherche Médicale U1056/Université Toulouse III, Hôpital Purpan, Toulouse, France.
authors.forename: Sarra
authors.initials: S
authors.lastname: Zaafouri
authors.affiliation: Différenciation Epidermique et Autoimmunité Rhumatoïde, Centre National de la Recherche Scientifique UMR5165/Institut National de la Recherche Médicale U1056/Université Toulouse III, Hôpital Purpan, Toulouse, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jonca
authors.affiliation: Différenciation Epidermique et Autoimmunité Rhumatoïde, Centre National de la Recherche Scientifique UMR5165/Institut National de la Recherche Médicale U1056/Université Toulouse III, Hôpital Purpan, Toulouse, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Serre
authors.affiliation: Institut Clinique de la Souris, Illkirch, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Birling
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR7104/Institut National de la Santé et de la Recherche Médicale U964/Université de Strasbourg, Illkirch, France; University of Strasbourg Institute for Advanced Study, Strasbourg, France; Freiburg Institute for Advanced Studies, Freiburg, Germany. Electronic address: mei@igbmc.fr.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D015415:Biomarkers; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003872:Dermatitis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004817:Epidermis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins / Q000172:deficiency; D056747:Immunomodulation; D007249:Inflammation / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D053759:Interleukin-23 / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D015415:Biomarkers; C109656:CDSN protein, human; D016207:Cytokines; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D053759:Interleukin-23; D044464:Receptor, PAR-2; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse
keywords: Epidermal barrier; IL-1β; IL-23; T(H)17; T(H)2; atopic dermatitis; corneodesmosin; mouse model; peeling skin syndrome type B; skin inflammation; thymic stromal lymphopoietin