Control of the Physical and Antimicrobial Skin Barrier by an IL-31-IL-1 Signaling Network

• Published in: The Journal of immunology (1950) Vol. 196; no. 8; pp. 3233 - 3244
• Main Authors: Hänel, Kai H, Pfaff, Carolina M, Cornelissen, Christian, Amann, Philipp M, Marquardt, Yvonne, Czaja, Katharina, Kim, Arianna, Lüscher, Bernhard, Baron, Jens M
• Format: Journal Article
• Language: English
• Published: United States 15.04.2016
• Subjects: Animals; Antimicrobial Cationic Peptides - biosynthesis; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell Line; Dermatitis, Atopic - pathology; Humans; Interleukin 1 Receptor Antagonist Protein - pharmacology; Interleukin-1alpha - metabolism; Interleukin-1beta - metabolism; Interleukins - metabolism; Interleukins - pharmacology; Intermediate Filament Proteins - metabolism; Keratinocytes - cytology; Mice; Mice, Inbred NOD; Mice, SCID; Receptors, Interleukin-1 - antagonists & inhibitors; Signal Transduction - physiology; Skin - cytology; Skin - growth & development; Tight Junctions - drug effects; Tight Junctions - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1402943

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.