Atopic dermatitis and skin disease
A sensory neuron–expressed IL-31 receptor mediates T helper cell–dependent itch: Involvement of TRPV1 and TRPA1

https://doi.org/10.1016/j.jaci.2013.10.048Get rights and content

Background

Although the cytokine IL-31 has been implicated in inflammatory and lymphoma-associated itch, the cellular basis for its pruritic action is yet unclear.

Objective

We sought to determine whether immune cell–derived IL-31 directly stimulates sensory neurons and to identify the molecular basis of IL-31–induced itch.

Methods

We used immunohistochemistry and quantitative real-time PCR to determine IL-31 expression levels in mice and human subjects. Immunohistochemistry, immunofluorescence, quantitative real-time PCR, in vivo pharmacology, Western blotting, single-cell calcium imaging, and electrophysiology were used to examine the distribution, functionality, and cellular basis of the neuronal IL-31 receptor α in mice and human subjects.

Results

Among all immune and resident skin cells examined, IL-31 was predominantly produced by TH2 and, to a significantly lesser extent, mature dendritic cells. Cutaneous and intrathecal injections of IL-31 evoked intense itch, and its concentrations increased significantly in murine atopy-like dermatitis skin. Both human and mouse dorsal root ganglia neurons express IL-31RA, largely in neurons that coexpress transient receptor potential cation channel vanilloid subtype 1 (TRPV1). IL-31–induced itch was significantly reduced in TRPV1-deficient and transient receptor channel potential cation channel ankyrin subtype 1 (TRPA1)–deficient mice but not in c-kit or proteinase-activated receptor 2 mice. In cultured primary sensory neurons IL-31 triggered Ca2+ release and extracellular signal-regulated kinase 1/2 phosphorylation, inhibition of which blocked IL-31 signaling in vitro and reduced IL-31–induced scratching in vivo.

Conclusion

IL-31RA is a functional receptor expressed by a small subpopulation of IL-31RA+/TRPV1+/TRPA1+ neurons and is a critical neuroimmune link between TH2 cells and sensory nerves for the generation of T cell–mediated itch. Thus targeting neuronal IL-31RA might be effective in the management of TH2-mediated itch, including atopic dermatitis and cutaneous T-cell lymphoma.

Section snippets

Materials

Recombinant mouse IL-31 was provided by ZymoGenetics (Seattle, Wash). For details, see the Methods section in this article's Online Repository at www.jacionline.org.

Patients

Patients and healthy control subjects were included after providing written informed consent within a study protocol approved by the ethics committees of the University Hospital Muenster, Heinrich-Heine-University Düsseldorf, and University Hospital Göttingen, Germany. For details, see the Methods section in this article's Online

Production of IL-31 by human TH2 cells

Several studies have demonstrated that IL-31 is expressed by skin-homing TH2 cells during inflammation, most notably in patients with AD.6, 7, 19, 23 No study has systematically compared expression levels of IL-31 in all potentially relevant immune and permanent skin cells involved in AD. Using qPCR,20 we compared expression levels of IL-31 and its receptor, IL-31RA, in various immune and permanent skin cells of patients with AD and psoriasis. Skin specimens were obtained from healthy donors

Discussion

The resistance of prevalent pruritic diseases to antihistamines, as exemplified by AD, argues strongly for the existence of histamine-independent pruritic pathways that are important targets for therapy of chronic itch.11, 12, 13 We demonstrate that IL-31 induces itch by directly activating IL-31RA on TRPV1+/TRPA1+ sensory nerves in the skin. We show that TH2 cells are the predominant cellular source of IL-31 and that the number and activation of TH2 cells, as well as IL-31 levels, are

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    Supported by grants from the National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; AR059402), Deutsche Forschungsgemeinschaft (DFG; Ste1014/2-2), IZKF Muenster (STE3/034/07), and CE.R.I.E.S. Paris (to M.S.); NIH NS14627 (to A.B.); NIH AR057194 (to E.C.); DFG Ce165/1-1 (to F.C.); DFG Ke1672/1-1 (to C.K.); and DFG (Ho2092/4-1) and DFG-FOR729 (Ho2092/5-2; to B.H.).

    Disclosure of potential conflict of interest: C. Kempkes, M. Feld, and B. Homey have been supported by one or more grants from Deutsche Forschungsgemaeinschaft (the German Research Foundation). A. Ikoma is employed by Galderma Japan. S. R. Dillon has received research support from and is employed by ZymoGenetics (a wholly owned subsidiary of Bristol-Meyers Squibb) and owns stock/stock options in Bristol-Meyers Squibb. A. Basbaum has received research support from the National Institutes of Health (NIH). M. Steinhoff has received research support from the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and BMS/Zymogenetics. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

    Co-senior authors.

    §

    Also affiliated with the Clinic of Dermatology and Allergology, University Medical Center, Goettingen, Germany.

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