Atopic dermatitis, a highly pruritic chronic inflammatory disorder, is characterised by a TH₂-mediated immune response. Activated skin-homing (CLA+) TH₂ cells in patients with atopic dermatitis produce higher levels of IL-31 than controls (Bilsborough et al. 2006). IL-31 mRNA is upregulated in murine models of atopic dermatitis, including an ovalbumin (OVA)-induced model and a model induced by topical application of superantigen Staphylococcus aureus toxin B (SEB) (Cevikbas et al. 2014). IL-31 overexpression in transgenic mice induces an atopic-like dermatitis (Dillon et al. 2004; Grimstad et al. 2009). IL 31 injected into mice induces pruritus (Arai et al. 2013) and alopecia (Dillon et al. 2004) but not pain (Cevikbas et al. 2014). Interestingly, IL-31-induced alopecia is dependent on the presence of functioning lymphocytes, while IL-31-induced pruritus is not (Dillon et al. 2004). Cutaneous (Dillon et al. 2004) as well as intrathecal (Cevikbas et al. 2014) injections induce itch. The effect of intrathecal injection, in bypassing the skin, suggests that IL-31 can hypothetically trigger pruritus centrally in a direct fashion. Whether this is relevant in certain pathophysiologies remains to be determined. Cutaneous injection of IL-31 induced pruritus after 3–4 days in mice, and pruritus persisted for 6–9 days after administration had ceased (Dillon et al. 2004). One recent study in humans indicated that IL-31 does not induce an immediate itch following a skin challenge (Hawro et al. 2014). Of note, in a further study, the clinically relevant pruritic effect of injected IL-31 occurred despite only 4 % of DRGs being IL-31RA⁺(Cevikbas et al. 2014). The delayed onset and sustained nature of IL-31-induced pruritus (Arai et al. 2013) is characteristic of C-fibre activation. A Japanese team of researchers demonstrated both delayed itch in mice injected with intravenous IL-31, and also that intravenously administered IL-31R antibody reduced itch (Kasutani et al. 2014). In that study, the authors used two dermatitis models: firstly, a contact sensitivity reaction model and, secondly, a chronic AD-like model. They found that IL-31R antibody reduced itch both when used in a preventative manner and also after the disease was established. In the chronic AD-like model, IL-31R antibody reduced ear swelling and the dermatitis score. Existing drugs, including glucocorticoids, naloxone, calcineurin inhibitors (tacrolimus and pimecrolimus) and the H1 receptor antagonist, terfenadine, did not impact IL-31-induced itch (Kasutani et al. 2014). This supports the findings of a murine study in which IL-31-induced pruritus was unchanged in mast cell-deficient c-kit mutant mice compared to wild-type controls, indicating that neither histamine nor tryptase, pruritogens released from mast cells, is required for IL-31-mediated itch (Cevikbas et al. 2014). In a separate study, anti-IL-31 antibodies reduced itch in a murine model of atopic dermatitis (Grimstad et al. 2009) suggesting that an anti-IL-31/IL-31 blocking strategy may be beneficial to treat itch in atopic dermatitis.

Patients with AD express higher levels of IL-31 in their skin (Nobbe et al. 2012). IL-31 is upregulated in pruritic skin in AD compared with non-pruritic skin affected by psoriasis (Neis et al. 2006; Sonkoly et al. 2006). In patients with AD, IL-31 levels are higher in lesional compared to non-lesional skin. However, levels of IL-31 RNA are nonetheless fourfold higher in non-lesional skin of AD patients compared to skin of healthy controls (Sonkoly et al. 2006). The highest levels of IL-31 are seen in prurigo nodularis, a condition characterised by severe pruritus (Sonkoly et al. 2006). A haplotype of the IL-31 gene is associated with atopic dermatitis in humans. The high levels of IL-31 associated with CD3⁺ CD4⁺ CD26⁻ T-lymphocytes, the cell type having undergone malignant transformation in cutaneous T-cell lymphoma, may shed light on the mechanism of itch in that disorder (Singer et al. 2013).

As previously outlined, IL-31 is upregulated in pruritic skin disorders. One trigger identified for this upregulation is the exposure to staphylococcal superantigens, and while upregulation occurs in the peripheral blood monocytes of both AD patients and healthy controls, the increase is greater in AD patients (Sonkoly et al. 2006). IL-31, an immune system-derived cytokine, is capable of “crosstalk” with the nervous system. The highest level of expression of the IL-31 receptor is on DRGs. IL-31-induced pruritus is significantly reduced in TRPV1- and TRPA1-deficient mice, and additionally, IL-31RA is largely expressed on neurons that also express TRPV1 (Cevikbas et al. 2014). Only a subset of neurons expressing TRPV1 express IL-31RA (Cevikbas et al. 2014). The co-localisation of IL-31RA and TRPV1 is of functional significance as following intradermal IL-31 injections scratching behaviour was reduced in TRPV1 knockout mice and following intrathecal injection scratching behaviour was similarly reduced following capsaicin-mediated TRPV1 neuronal ablation (Cevikbas et al. 2014). IL-31 has been demonstrated to trigger intracellular Ca²⁺ influx, which is in someway TRPV1/TRPA1 dependent (Cevikbas et al. 2014). TRPA1 is a channel required for mas-related G protein-coupled receptor (Mrgpr) and endothelin-1 (ET-1)-mediated itch. IL-31-mediated itch is reduced in TRPA1 knockout mice (Cevikbas et al. 2014). In vitro evidence of IL-31 acting via ERK1/2 phosphorylation is supported by in vivo reduction in scratching behaviour in the setting of a specific inhibitor of ERK1/2 activation (Cevikbas et al. 2014).

IL-31-induced pruritus is independent of IgE (Dillon et al. 2004). Similarly, IL-31-mediated itch is independent of the mast cell-derived pruritogens, histamine and tryptase, and is similarly independent of the PAR-2 pathway (Cevikbas et al. 2014). Of IL-31 responsive neurons, 67 % are also responsive to capsaicin, 30 % to allyl isothiocyanate (AITC), 38 % to histamine and 21 % to PAR-2. The fact that 90 % of IL-31-responsive neurons also respond to chloroquine, an exogenous pruritogen which functions through the MrgprA3 receptor, is of unclear significance but is possibly related to the co-localisation of IL-31R and TRPA1, as TRPA1 is a channel required for mas-related G protein-coupled receptor (Mrgpr). MrgprA3 KO mice could be used to assess if this channel functions in IL-31-mediated itch.

IL-31 activates the MAPK, P13K/AKT and JAK/Stat pathway (STAT1, STAT3 and STAT 5) (Dillon et al. 2004; Ghilardi et al. 2002; Diveu et al. 2004; Dreuw et al. 2004).

Genetic variation may predispose some of us to IL-31-mediated itch, with a G allele variant of IL-31 associated with higher rates of non-atopic dermatitis (Schulz et al. 2007).

The delayed itch response after IL-31 injection seems incompatible with direct activation of IL-31R as the sole mechanism behind IL-31-mediated itch. IL-31 receptors are present on keratinocytes, eosinophils (Cheung et al. 2010), mast cells (Yamaoka et al. 2009), activated monocytes and macrophages (Bilsborough et al. 2006; Kasraie et al. 2010) in addition to neuronal cells such as DRGs; therefore, tissue-specific knockout studies are required to assess the relative contribution of these tissue types to IL-31-mediated itch.

Of particular interest is the role that keratinocytes play in IL-31-mediated itch. Keratinocytes express the IL-31 receptor. Intriguingly, IL-31RA is upregulated in the keratinocytes of patients with AD compared to controls (Bilsborough et al. 2006), suggesting that these patients are primed to respond to IL-31. Whether this is a cause or effect of their condition is unclear. Keratinocytes play an active role in modulating the neuronal experience of pain and pruritus, at least in part, through the release of mediators such as neurotrophins, neuropeptides or proteases (Paus et al. 2006; Steinhoff et al. 2006). IL-31 induces keratinocyte-associated inflammatory chemokines such as CXCL1, CCL17 and CCL22 (Dillon et al. 2004) and thymic stromal lymphopoietin (TSLP). Keratinocytes release IL-1 and IL-6, which may play a role in neuronal communication and pruritus. A study assessing IL-31 administration in the setting of keratinocyte-specific IL-31RA knockout would provide useful insight into the significance of their role.

There are myriad signalling pathways in afferent neurons, activated by a range of pruritogens, and the specificity of the process perhaps depends on the combination of signalling pathways engaged by a given pruritogen.

Oncostatin M (OSM) is a cytokine that belongs to the IL-6 family. It plays a critical role in inflammation, autoimmunity and in cancer (Silver and Hunter 2010), with a loss of responsiveness to OSM linked to disease progress in cancer patients (Lacreusette et al. 2007). OSM mRNA has been detected in various tissues in the human body, including T cells, neutrophils, eosinophils as well as microglia in the central nervous system (Repovic and Benveniste 2002; Tamura et al. 2002). OSM released from T cells is a potent stimulator of keratinocyte migration, and OSM transcripts are enhanced in the skin of patients with atopic dermatitis, a pruritic skin disease (Boniface et al. 2007). OSM may play an essential role in the development of a subtype of nociceptive neuron in the dorsal root ganglia (Morikawa et al. 2004; Bando et al. 2006), suggesting that OSM may represent a link between nerves and T cells in the skin.

OSM shares the glycoprotein-130 signal-transducing receptor that forms part of the receptor complex for all of the IL-6 family (Silver and Hunter 2010). The OSM receptor (OSMR) is a member of the type 1 cytokine receptor family (Homey et al. 2006). Murine OSM binds to a selective heterodimer of the OSMR beta (OSMRβ) receptor and the glycoprotein-130 receptor family (Tanaka et al. 1999). The type I OSM receptor is identical to the leukaemia inhibitory factor receptor (LIFR beta) and gp130 heterodimer, and the type II OSM receptor consists of gp130 and the OSMRβ subunit (Tanaka et al. 1999). A missense mutation in the OSMRβ gene has been reported to occur in patients with familial primary localised cutaneous amyloidosis (Arita et al. 2008), an autosomal-dominant disorder associated with chronic pruritus. This suggests that OSMRβ plays an important role in human itch. There is little evidence at present to suggest that OSM has a direct role in the genesis of pruritus.

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine that is implicated in the pathogenesis of diseases characterised by TH2 responses, such as atopic dermatitis (Leyva-Castillo et al. 2013). TSLP acts as a potent stimulator of Th2 cytokines including IL 4, 5, and 13 with subsequent IgE production (Brandt and Sivaprasad 2011). Wilson et al. (2013) discovered that TSLP acts as a primary pruritogen, whereby calcium-dependent TSLP release by keratinocytes directly activates primary afferent sensory neurons as well as stimulating immune cells to induce itch and promote inflammatory responses in the skin. The authors identified the ORAI1/NFAT calcium signalling pathway as an essential regulator of TSLP release from keratinocytes in the skin. The TSLP receptor (TSLPR), a heterodimer of an IL-7 receptor alpha chain and a TSLP-specific receptor chain, is expressed in neuronal tissue in human dorsal root ganglia. These TSLP-sensitive neurons appear to represent a novel, distinct subset of neural tissue. TSLP acts directly on transient receptor potential (TRP) TRPA1-positive sensory neurons, which are downstream of TSLPR, to trigger itch. Histamine-dependent itch requires TRPV1 (Imamachi et al. 2009) but Wilson et al. (2013) showed that TRPV1-deficient mice displayed normal TSLP-evoked itch behaviours, indicating that TSLPR activation of primary afferent sensory neurons occurs independently of TRPV1. Wilson and colleagues showed that histamine, and other pruritogens, is not required to generate TSLP-evoked itch and that acute TSLP-evoked itch is independent of lymphocytes.

Cyclosporine is an inhibitor of NFAT-mediated transcription and is used in the management of pruritic inflammatory skin diseases, such as atopic dermatitis (Madan and Griffiths 2007). The authors suggest that the effectiveness of cyclosporine in treating chronic itch may be partially due to its effect on keratinocyte-mediated TSLP release (Wilson et al. 2013).

IL-4 and IL-13 are both cytokines produced by TH2 cells that play an important role in the development of atopic dermatitis (Hamid et al. 1994). There is evidence that IL-4 is involved in the development of pruritus. Chan et al. (2001) showed that transgenic mice expressing epidermal IL-4 at the basal keratinocytes spontaneously developed a pruritic inflammatory skin disease reproducing all of the key features of human atopic dermatitis. A recent murine model in atopic-like mice showed that IL-4 was significantly upregulated in the skin following the application of the superantigen, Staphylococcus aureus toxin B (Cevikbas et al. 2014). These indicate that IL-4 may play an important role in the development of pruritus and inflammation in atopic dermatitis. Levels of IL-4, as well as IL-13, have been shown to correlate with levels of IL-31, a known pruritogen, in skin biopsies of patients with atopic dermatitis (Neis et al. 2006).

A transgenic murine study showed that the dermal expression of IL-13 in the skin resulted in a chronic pruritic inflammatory skin condition resembling eczema (Zheng et al. 2009). There are no studies demonstrating that IL-13 plays a direct role in the development of pruritus.