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

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 2; pp. 448 - 460.e7
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.02.2014; Elsevier; Elsevier Limited
• Subjects: Allergic diseases; Allergy and Immunology; Animals; atopic dermatitis; Biological and medical sciences; Calcium Channels - immunology; Cell culture; Cells, Cultured; Cytokine; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Ganglia, Spinal - cytology; Human subjects; Humans; Immunopathology; Interleukins - immunology; Lymphoma; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mineral oils; Nerve Tissue Proteins - immunology; Neurons; Pruritus - immunology; Psoriasis; Receptors, Interleukin - genetics; Receptors, Interleukin - immunology; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; sensory nerve; Sensory Receptor Cells - immunology; skin; Skin - immunology; Skin allergic diseases. Stinging insect allergies; Skin diseases; Spinal cord; Th2 Cells - immunology; transient receptor potential channel; Transient Receptor Potential Channels - immunology; TRPA1 Cation Channel; TRPV Cation Channels - genetics; TRPV Cation Channels - immunology; skin; atopic dermatitis; AITC; OSMRβ; GRPR; SC; qPCR; transient receptor potential channel; hpf; PAR-2; AD; KO; TRPA1; Cytokine; TRPV1; SEB; MEK; TG; NPR-A; Mrgpr; sensory nerve; DRG; IB4; HBSS; OVA; ERK; Spinal cord; Proteinase-activated receptor 2; Oncostatin M receptor β; Allyl isothiocyanate; Natriuretic peptide receptor A; Mitogen-activated protein kinase enzyme; Dorsal root ganglia; Ovalbumin; Quantitative real-time PCR; Transient receptor channel potential cation channel ankyrin subtype 1; High-power field; Extracellular signal-regulated kinase; Transient receptor potential cation channel vanilloid subtype 1; Mas-related G protein–coupled receptor; Knockout; Gastrin-releasing peptide receptor; Hanks balanced salt solution; Isolectin B4; Staphylococcal enterotoxin B; Trigeminal ganglion; Allergy; Immunopathology; Skin disease; Helper cell; Ionic channel; Pruritus; Transitory; Atopy; Immunology; Neuron; Atopic dermatitis; Interleukin 31; T-Lymphocyte; Sensory nerve; Skin; Biological receptor
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2013.10.048

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