A Sensory Neuron-expressed Interleukin-31 Receptor Mediates T helper Cell-dependent Itch: Involvement of TRPV1 and TRPA1
By F. Cevikbas, Xidao Wang, T. Akiyama, C. Kempkes, T. Savinko, A. Antal, G. Kukova, T. Buhl, A. Ikoma, Joerg Buddenkotte and 8 more. Journal of Allergy and Clinical Immunology, 2013
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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.
Subfields: Dermatology, Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/43038cd3a98a23d4a5a7b68bb6e103a6bee6e89a
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Citations in the corpus
- Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases. (2016, background): “IL-31RA is a functional receptor expressed by a small subpopulation of IL-31Ra(1)/TRPV1(1)/TRPA1(1) neurons and is a critical neuroimmune link between TH2 cells and sensory nerves for the generation of T cell–mediated itch.(144) Transgenic overexpression of IL-31 inmice results in a phenotype that r”
- Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch (2017, neutral): “For example, the pruritogen histamine is associated with acute itch in the setting of urticaria (Kaplan, 2004), and interleukin (IL)-31, a previously identified cytokine pruritogen, has been linked to AD-associated itch (Cevikbas et al., 2014; Dillon et al., 2004; Ruzicka et al., 2017; Sonkoly et al”