A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch

Involvement of TRPV1 and TRPA1

Ferda Cevikbas, Xidao Wang, Tasuku Akiyama, Cordula Kempkes, Terhi Savinko, Attila Antal, Gabriela Kukova, Timo Buhl, Akihiko Ikoma, Joerg Buddenkotte, Vassili Soumelis, Micha Feld, Harri Alenius, Stacey R. Dillon, Earl Carstens, Bernhard Homey, Allan Basbaum, Martin Steinhoff

Research output: Contribution to journalArticle

208 Citations (Scopus)

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 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.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
Volume133
Issue number2
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Transient Receptor Potential Channels
Sensory Receptor Cells
Helper-Inducer T-Lymphocytes
Neurons
Skin
Real-Time Polymerase Chain Reaction
Immunohistochemistry
PAR-2 Receptor
Ankyrins
Cutaneous T-Cell Lymphoma
Spinal Injections
Mitogen-Activated Protein Kinase 3
Electrophysiology
Mitogen-Activated Protein Kinase 1
Spinal Ganglia
Dermatitis
Atopic Dermatitis
Dendritic Cells
Fluorescent Antibody Technique
Lymphoma

Keywords

  • atopic dermatitis
  • Cytokine
  • sensory nerve
  • skin
  • transient receptor potential channel

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch : Involvement of TRPV1 and TRPA1. / Cevikbas, Ferda; Wang, Xidao; Akiyama, Tasuku; Kempkes, Cordula; Savinko, Terhi; Antal, Attila; Kukova, Gabriela; Buhl, Timo; Ikoma, Akihiko; Buddenkotte, Joerg; Soumelis, Vassili; Feld, Micha; Alenius, Harri; Dillon, Stacey R.; Carstens, Earl; Homey, Bernhard; Basbaum, Allan; Steinhoff, Martin.

In: Journal of Allergy and Clinical Immunology, Vol. 133, No. 2, 01.01.2014.

Research output: Contribution to journalArticle

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, SR, 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', Journal of Allergy and Clinical Immunology, vol. 133, no. 2. https://doi.org/10.1016/j.jaci.2013.10.048
Cevikbas, Ferda ; Wang, Xidao ; Akiyama, Tasuku ; Kempkes, Cordula ; Savinko, Terhi ; Antal, Attila ; Kukova, Gabriela ; Buhl, Timo ; Ikoma, Akihiko ; Buddenkotte, Joerg ; Soumelis, Vassili ; Feld, Micha ; Alenius, Harri ; Dillon, Stacey R. ; Carstens, Earl ; Homey, Bernhard ; Basbaum, Allan ; Steinhoff, Martin. / A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch : Involvement of TRPV1 and TRPA1. In: Journal of Allergy and Clinical Immunology. 2014 ; Vol. 133, No. 2.
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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 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.",
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T1 - A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch

T2 - 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

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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 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.

AB - 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.

KW - atopic dermatitis

KW - Cytokine

KW - sensory nerve

KW - skin

KW - transient receptor potential channel

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