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A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1.
J Allergy Clin Immunol. 2014 Feb; 133(2):448-60.JA

Abstract

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 Ca(2+) 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.

Authors+Show Affiliations

Departments of Dermatology and Surgery, University of California, San Francisco, San Francisco, Calif; Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.Department of Anatomy and the W.M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, Calif.Department of Neurobiology, Physiology and Behavior, University of California, Davis, Calif.Departments of Dermatology and Surgery, University of California, San Francisco, San Francisco, Calif.Unit of Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland.Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.Departments of Dermatology and Surgery, University of California, San Francisco, San Francisco, Calif.Departments of Dermatology and Surgery, University of California, San Francisco, San Francisco, Calif.Department of Dermatology, University Hospital Münster, Muenster, Germany.Department of Immunology, Institut Curie, Paris, France.Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.Unit of Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland.ZymoGenetics (a Bristol-Myers Squibb Company), Seattle, Wash.Department of Neurobiology, Physiology and Behavior, University of California, Davis, Calif.Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany. Electronic address: bernhard.homey@uni-duesseldorf.de.Department of Anatomy and the W.M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, Calif. Electronic address: Allan.Basbaum@ucsf.edu.Departments of Dermatology and Surgery, University of California, San Francisco, San Francisco, Calif; Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany. Electronic address: SteinhoffM@derm.ucsf.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24373353

Citation

Cevikbas, Ferda, et al. "A Sensory Neuron-expressed IL-31 Receptor Mediates T Helper Cell-dependent Itch: Involvement of TRPV1 and TRPA1." The Journal of Allergy and Clinical Immunology, vol. 133, no. 2, 2014, pp. 448-60.
Cevikbas F, Wang X, Akiyama T, et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1. J Allergy Clin Immunol. 2014;133(2):448-60.
Cevikbas, F., Wang, X., Akiyama, T., Kempkes, C., Savinko, T., Antal, A., Kukova, G., Buhl, T., Ikoma, A., Buddenkotte, J., Soumelis, V., Feld, M., Alenius, H., Dillon, S. R., Carstens, E., Homey, B., Basbaum, A., & Steinhoff, M. (2014). A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1. The Journal of Allergy and Clinical Immunology, 133(2), 448-60. https://doi.org/10.1016/j.jaci.2013.10.048
Cevikbas F, et al. A Sensory Neuron-expressed IL-31 Receptor Mediates T Helper Cell-dependent Itch: Involvement of TRPV1 and TRPA1. J Allergy Clin Immunol. 2014;133(2):448-60. PubMed PMID: 24373353.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1. AU - Cevikbas,Ferda, AU - Wang,Xidao, AU - Akiyama,Tasuku, AU - Kempkes,Cordula, AU - Savinko,Terhi, AU - Antal,Attila, AU - Kukova,Gabriela, AU - Buhl,Timo, AU - Ikoma,Akihiko, AU - Buddenkotte,Joerg, AU - Soumelis,Vassili, AU - Feld,Micha, AU - Alenius,Harri, AU - Dillon,Stacey R, AU - Carstens,Earl, AU - Homey,Bernhard, AU - Basbaum,Allan, AU - Steinhoff,Martin, Y1 - 2013/12/25/ PY - 2013/03/29/received PY - 2013/10/18/revised PY - 2013/10/23/accepted PY - 2013/12/31/entrez PY - 2014/1/1/pubmed PY - 2014/5/14/medline KW - AD KW - AITC KW - Allyl isothiocyanate KW - Atopic dermatitis KW - Cytokine KW - DRG KW - Dorsal root ganglia KW - ERK KW - Extracellular signal-regulated kinase KW - GRPR KW - Gastrin-releasing peptide receptor KW - HBSS KW - Hanks balanced salt solution KW - High-power field KW - IB4 KW - Isolectin B4 KW - KO KW - Knockout KW - MEK KW - Mas-related G protein–coupled receptor KW - Mitogen-activated protein kinase enzyme KW - Mrgpr KW - NPR-A KW - Natriuretic peptide receptor A KW - OSMRβ KW - OVA KW - Oncostatin M receptor β KW - Ovalbumin KW - PAR-2 KW - Proteinase-activated receptor 2 KW - Quantitative real-time PCR KW - SC KW - SEB KW - Spinal cord KW - Staphylococcal enterotoxin B KW - TG KW - TRPA1 KW - TRPV1 KW - Transient receptor channel potential cation channel ankyrin subtype 1 KW - Transient receptor potential cation channel vanilloid subtype 1 KW - Trigeminal ganglion KW - atopic dermatitis KW - hpf KW - qPCR KW - sensory nerve KW - skin KW - transient receptor potential channel SP - 448 EP - 60 JF - The Journal of allergy and clinical immunology JO - J Allergy Clin Immunol VL - 133 IS - 2 N2 - 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 Ca(2+) 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. SN - 1097-6825 UR - https://www.unboundmedicine.com/medline/citation/24373353/A_sensory_neuron_expressed_IL_31_receptor_mediates_T_helper_cell_dependent_itch:_Involvement_of_TRPV1_and_TRPA1_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-6749(13)01710-7 DB - PRIME DP - Unbound Medicine ER -