A Sensory Neuron-expressed Interleukin-31 Receptor Mediates T helper Cell-dependent Itch: Involvement of TRPV1 and TRPA1
nihms540721
Ferda Cevikbas, PhD1,5,*, Xidao Wang, PhD2,*, Tasuku Akiyama, PhD3, Cordula Kempkes, PhD1, Terhi Savinko, PhD4, Attila Antal, MD5, Gabriela Kukova, MD5, Timo Buhl, MD1, Akihiko Ikoma, MD, PhD1, Joerg Buddenkotte, PhD6, Vassili Soumelis, MD7, Micha Feld, PhD5, Harri Alenius, PhD4, Stacey R. Dillon, PhD8, Earl Carstens, PhD3, Bernhard Homey, MD5,#,§, Allan Basbaum, PhD2,#,§, and Martin Steinhoff, MD, PhD1,5,#,§
1Depts. of Dermatology and Surgery, University of California San Francisco, San Francisco, CA, USA 2Depts. of Anatomy and W.M. Keck Foundation Center for Integrative Neuroscience, University California San Francisco, San Francisco, CA, USA 3Dept. of Neurobiology, University California Davis, CA, USA 4Unit of Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland 5Dept. of Dermatology, University Hospital Duesseldorf, Duesseldorf, Germany 6Dept. of Dermatology, University Hospital Muenster, Muenster Germany 7Dep. of Immunology, Institut Curie, Paris, France 8ZymoGenetics, Inc. (a Bristol-Myers Squibb Company) Seattle, WA, USA
Abstract
Background—Although the cytokine, interleukin-31 (IL-31), has been implicated in
inflammatory and lymphoma-associated itch, the cellular basis for its pruritic action is yet unclear.
Objective—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 qRTPCR to determine IL-31 expression levels in mice and humans. Immunohistochemistry, immunofluorescence, qRTPCR, in vivo pharmacology, western blotting, single cell calcium and electrophysiology were used to examine the distribution, functionality and cellular basis of the neuronal IL-31 receptor (IL-31RA) in mice and humans.
Results—Among all immune and resident skin cells examined, IL-31 was predominantly produced by TH2 and to a significantly lesser extend by mature dendritic cells. Cutaneous and intrathecal injections of IL-31 evoked intense itch, and its concentration increased significantly in murine atopic-like dermatitis skin. Both human and mouse DRG neurons express IL-31RA, largely in neurons that co-express TRPV1. IL-31-induced itch was significantly reduced in TRPV1- and TRPA1-deficient mice, not c-kit or PAR-2 mice. In cultured primary sensory neurons, IL-31 triggered Ca2+-release and ERK1/2 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 neuro-immune link between TH2 cells and sensory nerves for the generation of T cell-mediated itch. Thus, targeting neuronal IL-31RA may be effective in the management of TH2-mediated itch, including atopic dermatitis and cutaneous T cell lymphoma.
Keywords
cytokine; atopic dermatitis; sensory nerve; skin; TRP channel
© 2013 American Academy of Allergy, Asthma and Immunology. Published by Mosby, Inc. All rights reserved.
#Addresses for correspondence: Martin Steinhoff, M.D., Ph.D., Departments of Dermatology and Surgery, University of California, San Francisco, 513 Parnassus Ave, Room S-1268, San Francisco, CA, 94143 USA, Phone: +1 415 476 6978, FAX: +1 415 476 0936, SteinhoffM@derm.ucsf.edu. Allan. I. Basbaum, Ph.D., Department of Anatomy, University of California, San Francisco, 1550 4th Street, San Francisco, CA, USA, Phone: +1 415 476 5270, FAX: +1 415 476 1974, Allan.Basbaum@ucsf.edu. Bernhard Homey, M.D.. Department of Dermatology. University Hospital Duesseldorf, Duesseldorf, Germany, Phone: +49 211 811 7600, FAX: +49 211 811 7316, bernhard.homey@uni-duesseldorf.de.
*contributed equally to this work; §Co-senior authors;
Author contribution:
F. C.: conducted most of the experiments, designed the study, wrote manuscript. X. W.: conducted in vivo and morphological experiments with F.C. T.A: performed single cell calcium measurement and electrophysiology recordings under supervision of E.C; T. S.: designed the study for the in vivo mouse models of AD under supervision of H.A; A.A, M.F.: performed human staining experiments of skin tissue and qPCR of cells under supervision of B.H.; C. K.: performed western blotting and wrote part of the manuscript; G. K.: performed human staining experiments of skin tissue and qPCR of cells; A. I.: assisted in cheek model assay; T. B.: stained human DRG for IL-31RA; H. A.: supervised the murine AD study; S. D.: supervised vivo mouse studies; E. C.: supervised electrophysiology study; B. H.: designed, supervised human IL-31 studies and mouse atopy models, and wrote manuscript; A.I.B.: designed, supervised the neuronal experiments, and wrote manuscript; M.S.: designed, supervised all experiments, analyzed data, and wrote manuscript.
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