1. A sensory neuron–expressed IL-31 receptor mediates T helper cell–dependent itch: Involvement of TRPV1 and TRPA1.
- Author
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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, and Steinhoff, Martin
- 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 T
H 2 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 TH 2 cells and sensory nerves for the generation of T cell–mediated itch. Thus targeting neuronal IL-31RA might be effective in the management of TH 2-mediated itch, including atopic dermatitis and cutaneous T-cell lymphoma. [Copyright &y& Elsevier]- Published
- 2014
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