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.

Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucineenkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide-and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.

Rosacea is a common skin disease with a high impact on quality of life. Characterized by erythema, edema, burning pain, immune infiltration, and facial skin fibrosis, rosacea has all the characteristics of neurogenic inflammation, a condition induced by sensory nerves via antidromically released neuromediators. To investigate the hypothesis of a central role of neural interactions in the pathophysiology, we analyzed molecular and morphological characteristics in the different subtypes of rosacea by immunohistochemistry, double immunofluorescence, morphometry, real-time PCR, and gene array analysis, and compared the findings with those for lupus erythematosus or healthy skin. Our results showed significantly dilated blood and lymphatic vessels. Signs of angiogenesis were only evident in phymatous rosacea. The number of mast cells and fibroblasts was increased in rosacea, already in subtypes in which fibrosis is not clinically apparent, indicating early activation. Sensory nerves were closely associated with blood vessels and mast cells, and were increased in erythematous rosacea. Gene array studies and qRT-PCR confirmed upregulation of genes involved in vasoregulation and neurogenic inflammation. Thus, dysregulation of mediators and receptors implicated in neurovascular and neuroimmune communication may be crucial at early stages of rosacea. Drugs that function on neurovascular and/or neuroimmune communication may be beneficial for the treatment of rosacea.