The pruritus- and TH2-associated cytokine Interleukin-31 promotes growth of sensory nerves

Publication date: Available online 6 April 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Micha Feld, Richard Garcia, Jörg Buddenkotte, Shintaro Katayama, Katherine Lewis, Gareth Muirhead, Peter Hevezi, Kristin Plesser, Holger Schrumpf, Kaarel Krjutshkov, Olga Sergeeva, Hans Werner Müller, Sophia Tsoka, Juha Kere, Stacey R. Dillon, Martin Steinhoff, Bernhard Homey
BackgroundPruritus 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.ObjectiveTo analyze the IL-31-related transcriptome in sensory neurons and to investigate whether IL-31 promotes sensory nerve fiber outgrowth.MethodsIn 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.ResultsTransgenic Il31-overexpression and s.c. delivered IL-31 induced an increase in the cutaneous nerve fiber density in lesional skin in vivo. Transcriptional profiling of IL-31-activated DRG neurons revealed enrichment for genes promoting nervous system development, neuronal outgrowth and negatively regulating cell death. Moreover, the growth cones of primary small diameter DRG neurons showed abundant IL-31RA expression. Indeed, IL-31 selectively promoted nerve fiber extension only in small diameter neurons. STAT3 phosphorylation mediated IL-31-induced neuronal outgrowth and pharmacological inhibition of STAT3 completely abolished this effect. In contrast, TRPV1 channels were dispensable for IL-31-induced neuronal sprouting.ConclusionsThe pruritus- and TH2-associated novel cytokine IL-31 induces a distinct transcriptional program in sensory neurons leading to nerve elongation and branching in vitro and in vivo. This finding might help to understand the clinical observation that patients with AD experience increased sensitivity to minimal stimuli inducing sustained itch.

Teaser

The pruritus- and TH2-associated novel cytokine IL-31 induces a distinct transcriptional program in sensory neurons leading to nerve elongation and branching in vitro and in vivo that may explain enhanced sensitivity of AD patients towards pruritus trigger factors.


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