title: Control of the Physical and Antimicrobial Skin Barrier by an IL-31-IL-1 Signaling Network.
abstract: Atopic dermatitis, a chronic inflammatory skin disease with increasing prevalence, is closely associated with skin barrier defects. A cytokine related to disease severity and inhibition of keratinocyte differentiation is IL-31. To identify its molecular targets, IL-31-dependent gene expression was determined in three-dimensional organotypic skin models. IL-31-regulated genes are involved in the formation of an intact physical skin barrier. Many of these genes were poorly induced during differentiation as a consequence of IL-31 treatment, resulting in increased penetrability to allergens and irritants. Furthermore, studies employing cell-sorted skin equivalents in SCID/NOD mice demonstrated enhanced transepidermal water loss following s.c. administration of IL-31. We identified the IL-1 cytokine network as a downstream effector of IL-31 signaling. Anakinra, an IL-1R antagonist, blocked the IL-31 effects on skin differentiation. In addition to the effects on the physical barrier, IL-31 stimulated the expression of antimicrobial peptides, thereby inhibiting bacterial growth on the three-dimensional organotypic skin models. This was evident already at low doses of IL-31, insufficient to interfere with the physical barrier. Together, these findings demonstrate that IL-31 affects keratinocyte differentiation in multiple ways and that the IL-1 cytokine network is a major downstream effector of IL-31 signaling in deregulating the physical skin barrier. Moreover, by interfering with IL-31, a currently evaluated drug target, we will have to consider that low doses of IL-31 promote the antimicrobial barrier, and thus a complete inhibition of IL-31 signaling may be undesirable.
authors.affiliation: Department of Dermatology and Allergology, Medical School, RWTH Aachen University, 52074 Aachen, Germany; Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany; and.
authors.forename: Kai H
authors.initials: KH
authors.lastname: Hänel
authors.affiliation: Department of Dermatology and Allergology, Medical School, RWTH Aachen University, 52074 Aachen, Germany; Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany; and.
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Pfaff
authors.affiliation: Department of Dermatology and Allergology, Medical School, RWTH Aachen University, 52074 Aachen, Germany; Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany; and.
authors.forename: Christian
authors.identifier: http://orcid.org/0000-0001-7983-657X
authors.initials: C
authors.lastname: Cornelissen
authors.affiliation: Department of Dermatology and Allergology, Medical School, RWTH Aachen University, 52074 Aachen, Germany;
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Amann
authors.affiliation: Department of Dermatology and Allergology, Medical School, RWTH Aachen University, 52074 Aachen, Germany;
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Marquardt
authors.affiliation: Department of Dermatology and Allergology, Medical School, RWTH Aachen University, 52074 Aachen, Germany;
authors.forename: Katharina
authors.identifier: http://orcid.org/0000-0002-1824-1318
authors.initials: K
authors.lastname: Czaja
authors.affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Arianna
authors.identifier: http://orcid.org/0000-0003-4609-1182
authors.initials: A
authors.lastname: Kim
authors.affiliation: Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany; and luescher@rwth-aachen.de jensmalte.baron@post.rwth-aachen.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
authors.affiliation: Department of Dermatology and Allergology, Medical School, RWTH Aachen University, 52074 Aachen, Germany; luescher@rwth-aachen.de jensmalte.baron@post.rwth-aachen.de.
authors.forename: Jens M
authors.identifier: http://orcid.org/0000-0002-1174-6946
authors.initials: JM
authors.lastname: Baron
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003876:Dermatitis, Atopic / Q000473:pathology*; D000091344:Filaggrin Proteins; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism* / Q000494:pharmacology; D007381:Intermediate Filament Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000166:cytology / Q000254:growth & development; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; D000091344:Filaggrin Proteins; C508584:IL1A protein, human; C508585:IL1B protein, human; C502187:IL31 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D007378:Interleukins; D007381:Intermediate Filament Proteins; D017472:Receptors, Interleukin-1