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

Abstract

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.

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

“…These data confirm a recent publication by Cevikbas et al showing that the pruritogenic cytokine IL-31 induces phosphorylation of ERK1/2, but not p38 (57). In contrast, the time course of ET-1-induced ERK1/2 activation in DRG neurons pretreated with the ECE-1 inhibitor SM-19712 resembled that of vehicle-treated probes ( Figure 4).…”

Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity

“…The MEs include genes for the oncostatin M receptor (Osmr), interleukin 31 receptor A (Il31ra), 5-hydroxytryptamine (serotonin) receptor 1F (Htr1f), neurotensin (Nts) and somatostatin (Sst, Supplementary information, Table S1). This network may be related to with itch because IL31RA mediates T-helper cell dependent itch [36], and OSMR acts as its heterodimer receptor [37]. The red module contains genes for peptides such as adenylate cyclase activating polypeptide 1 (Adcyap1, a hub gene; k ME = 0.908), galanin (Gal) and tachykinin 1 (Tac1).…”

“…C2, particularly C2-1, are MHNs (MI, IS) that express itch-related NPB [43], IL31RA [36] and proteinase-activated receptor 2 (PAR2) encoded by F2rl1 [44]. The thermal sensitivity of C2 correlates with the presence of Trpv1 and Trpv2 in the Nppb gene network and the role of NBP in thermal hyperalgesia [19,45].…”

Topically Administered Janus-Kinase Inhibitors Tofacitinib and Oclacitinib Display Impressive Antipruritic and Anti-Inflammatory Responses in a Model of Allergic Dermatitis

“…In particular, proinflammatory cytokines that use the JAK pathway, such as interferon-g and interleukin (IL)-2, IL-4, IL-6, IL-13, IL-21, and IL-23, have been implicated in inflammatory disease (O'Shea et al, 2004). In addition, T H 2-derived cytokines, including IL-31 and thymic stromal lymphopoietin (TSLP), are ligands for murine and human sensory nerves and have a critical function to evoke itch (Cevikbas et al, 2014). Because these cytokines also interact with JAK, several JAK inhibitors have received a lot of attention recently as a therapeutic agent for major pruritic inflammatory skin diseases (Cosgrove et al, 2013a,b;Fujii and Sengoku, 2013;Ports et al, 2013;Gonzales et al, 2014).…”