The atopic dermatitis-associated cytokine IL-31 controls keratinocyte physiology and filaggrin expression pivotal for skin barrier function

• Applicant: Professor Dr. Jens Malte Baron
• Subject Area: Dermatology
• Term: from 2011 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 206858601

• Final Report Year: 2016

Final Report 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 this study by using a newly developed 3-D organotypic skin model. 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 as demonstrated in various novel functional assays. Furthermore studies employing cell-sorted skin equivalents in SCID/NOD mice demonstrated enhanced transepidermal water loss following subcutaneous administration of IL-31. We also identified the IL-1 cytokine network as a downstream effector of IL-31 signaling. Anakinra, an IL-1 receptor 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 3-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 effects 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. Within this project we were able to describe for the first time the physiological role of IL-31 in healthy human skin and the dose dependent pathological role of IL-31 on various skin barrier structures in AD. In this project were able to discover that the IL-1α pathway is the major pathway responsible for mediating the effect of IL-31 on skin barrier function (not release of IL-20/-24 as suggested in the grant proposal). We also discovered the physiological function of IL-31 regulating the expression of various antimicrobial peptides important for a functional chemical barrier. Untersuchungen aus dem geförderten Projekt wurden mit folgenden Preisen ausgezeichnet: ADF/ECARF (Europäischen Stiftung für Allergieforschung) Award 2013; Mainzer Abstract-Preis der Deutschen Gesellschaft für Allergologie und Klinische Immunologie 2014; Mainzer Abstract-Preis der Deutschen Gesellschaft für Allergologie und Klinische Immunologie 2013; Mainzer Abstract-Preis der Deutschen Gesellschaft für Allergologie und Klinische Immunologie 2012; Research on Skin-Dryness Award 2012 (La Roche-Posay Laboratoire Dermatologique Deutschland); Promotionspreis der Medizinischen Fakultät der RWTH Aachen 2012.

Publications

• Ultraviolet B (UVB) radiation and reactive oxygen species (ROS) modulate IL-31 expression in T-lymphocytes, monocytes and dendritic cells. Br J Dermatol; 165(5):966-75, 2011
  Cornelissen C, Brans R, Czaja K, Skazik C, Marquardt Y, Zwadlo-Klarwasser G, Kim A, Bickers DR, Lüscher-Firzlaff J, Lüscher B, Baron JM
  
• Atopische Dermatitis: IL-31 reguliert Keratinozytendifferenzierung. Allergo J, 21(3): 152, 2012
  Baron JM
  
• IL-31 regulates differentiation and filaggrin expression in human organotypic skin models. J All Clin Immunol 129(2):426-433, 2012
  Cornelissen C, Marquardt Y, Czaja K, Wenzel J, Frank J, Lüscher-Firzlaff J, Lüscher B, Baron JM
  
• Signaling by IL-31 and functional consequences. Eur J Cell Biol, 91:552– 566, 2012
  Cornelissen C, Lüscher-Firzlaff J, Baron JM, Lüscher B
  
• Cytokines and the skin barrier. Int. J. Mol. Sci., 14(4):6720-45; 2013
  Hänel KH, Cornelissen C, Lüscher B, Baron JM
  
• Successful omalizumab treatment in chronic spontaneous urticaria is associated with lowering of serum IL-31 levels. J Eur Acad Dermatol Venereol. 2014 Nov 4
  Altrichter S, Hawro T, Hänel K, Czaja K, Lüscher B, Maurer M, Church MK, Baron JM
  
• Control of the physical and antimicrobial skin barrier by an IL-31 – IL-1 signaling network. J. Immunol, 2016 Mar 4. pii: 1402943 [Epub ahead of print]
  Hänel K, Pfaff CM, Cornelissen C, Amann PM, Marquardt, Y, Czaja K, Kim A, Lüscher B, Baron JM