title: The pruritus- and TH2-associated cytokine IL-31 promotes growth of sensory nerves.
abstract: Pruritus is a cardinal symptom of atopic dermatitis, and an increased cutaneous sensory network is thought to contribute to pruritus. Although the immune cell-IL-31-neuron axis has been implicated in severe pruritus during atopic skin inflammation, IL-31's neuropoietic potential remains elusive.
  
  
  
  We sought to analyze the IL-31-related transcriptome in sensory neurons and to investigate whether IL-31 promotes sensory nerve fiber outgrowth.
  
  
  
  In vitro primary sensory neuron culture systems were subjected to whole-transcriptome sequencing, ingenuity pathway analysis, immunofluorescence, and nerve elongation, as well as branching assays after IL-31 stimulation. In vivo we investigated the cutaneous sensory neuronal network in wild-type, Il31-transgenic, and IL-31 pump-equipped mice.
  
  
  
  Transgenic Il31 overexpression and subcutaneously delivered IL-31 induced an increase in the cutaneous nerve fiber density in lesional skin in vivo. Transcriptional profiling of IL-31-activated dorsal root ganglia neurons revealed enrichment for genes promoting nervous system development and neuronal outgrowth and negatively regulating cell death. Moreover, the growth cones of primary small-diameter dorsal root ganglia neurons showed abundant IL-31 receptor α expression. Indeed, IL-31 selectively promoted nerve fiber extension only in small-diameter neurons. Signal transducer and activator of transcription 3 phosphorylation mediated IL-31-induced neuronal outgrowth, and pharmacologic inhibition of signal transducer and activator of transcription 3 completely abolished this effect. In contrast, transient receptor potential cation channel vanilloid subtype 1 channels were dispensable for IL-31-induced neuronal sprouting.
  
  
  
  The pruritus- and TH2-associated novel cytokine IL-31 induces a distinct transcriptional program in sensory neurons, leading to nerve elongation and branching both in vitro and in vivo. This finding might help us understand the clinical observation that patients with atopic dermatitis experience increased sensitivity to minimal stimuli inducing sustained itch.
authors.affiliation: Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Micha
authors.initials: M
authors.lastname: Feld
authors.affiliation: ZymoGenetics (a Bristol-Myers Squibb Company), Seattle, Wash.
authors.forename: Richard
authors.initials: R
authors.lastname: Garcia
authors.affiliation: Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Buddenkotte
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Katayama
authors.affiliation: ZymoGenetics (a Bristol-Myers Squibb Company), Seattle, Wash.
authors.forename: Katherine
authors.initials: K
authors.lastname: Lewis
authors.affiliation: Department of Informatics, King's College London, London, United Kingdom.
authors.forename: Gareth
authors.initials: G
authors.lastname: Muirhead
authors.affiliation: Physiology and Biophysics, University of California, Irvine, Calif.
authors.forename: Peter
authors.initials: P
authors.lastname: Hevezi
authors.affiliation: Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Plesser
authors.affiliation: Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Schrumpf
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Kaarel
authors.initials: K
authors.lastname: Krjutskov
authors.affiliation: Department of Neurophysiology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Sergeeva
authors.affiliation: Molecular Neurobiology Laboratory, Neurology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Hans Werner
authors.initials: HW
authors.lastname: Müller
authors.affiliation: Department of Informatics, King's College London, London, United Kingdom.
authors.forename: Sophia
authors.initials: S
authors.lastname: Tsoka
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: ZymoGenetics (a Bristol-Myers Squibb Company), Seattle, Wash.
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Dillon
authors.affiliation: Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany; Department of Dermatology and UCD Charles Institute for Translational Dermatology, Dublin, Ireland.
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
authors.affiliation: Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany. Electronic address: bernhard.homey@uni-duesseldorf.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Homey
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009412:Nerve Fibers / Q000378:metabolism; D010766:Phosphorylation; D011537:Pruritus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism*; D012867:Skin / Q000276:immunology / Q000294:innervation / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*
chemical_list: C502187:IL31 protein, human; D007378:Interleukins; D050796:STAT3 Transcription Factor
keywords: IL-31; IL-31 receptor α; atopic dermatitis; cutaneous hyperinnervation; dorsal root ganglia; nerve growth