The pruritus- and T_H2-associated cytokine IL-31 promotes growth of sensory nerves

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• 作者：Micha Feld ; PhD^a ; Richard Garcia ; PhD^b ; Jö ; rg Buddenkotte ; PhD^a ; Shintaro Katayama ; PhD^c ; Katherine Lewis ; PhD^b ; Gareth Muirhead ; MSc^d ; Peter Hevezi ; PhD^e ; Kristin Plesser ; MSc^a ; Holger Schrumpf ; MSc^a ; Kaarel Krjutskov ; PhD^c ; Olga Sergeeva ; PhD^f ; Hans Werner Mü ; ller ; PhD^g ; Sophia Tsoka ; PhD^d ; Juha Kere ; MD ; PhD^c ; Stacey R. Dillon ; PhD^b ; Martin Steinhoff ; MD ; PhD^a ; ^h ; ^&lowast ; ; Bernhard Homey ; MD^a ; ^&lowast ; ; ^{bernhard.homey@uni-duesseldorf.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：IL-31 ; IL-31 receptor α ; dorsal root ganglia ; atopic dermatitis ; nerve growth ; cutaneous hyperinnervation
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：138
• 期：2
• 页码：500-508.e24
• 全文大小：4992 K

文摘

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.

Objective

We sought to analyze the IL-31–related transcriptome in sensory neurons and to investigate whether IL-31 promotes sensory nerve fiber outgrowth.

Methods

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.

Results

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.

Conclusions

The pruritus- and T_H2-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.