While histamine is commonly considered as the predominant mediator of itch, it is now apparent that histaminergic (as seen in urticaria) and non-histaminergic (such as atopic dermatitis) mechanisms can drive pruritus. While closely related, these two mechanisms appear to be independent of one another. In the skin, both mechanisms of pruritus have their own receptors and cutaneous nerve fibres, which continues into the central nervous system (CNS) where each has its own specialised tracts and neural structures (Mollanazar et al., 2016).
Chronic pruritus, as seen in atopic dermatitis, is induced by the nonhistaminergic pathway and is likely to be a consequence of multiple factors related to skin barrier dysfunction. Transepidermal water loss (TEWL) increases following skin barrier dysfunction due to a reduction in keratinocyte retention of water and increased loss of water from the surrounding epidermal environment (Loden, 2012). Increased TEWL has been associated with itch intensity and has also been shown to increase the pH of the skin resulting in activation of serine proteases that promote further pruritus (Ny & Egelrud, 2004; Lee et al., 2006). In fact, in atopic dermatitis, the receptor for proteases is typically upregulated and sensitised (Mollanazar et al., 2016).
Skin barrier dysfunction is also likely to allow increased entry of irritants and pruritogens, which further enhance the itch process. Upon entry to the skin, these compounds are capable of stimulating one of myriad receptors on the keratinocyte cell surface channels (such as PAR2, TRPV ion channels, IL-31 receptor, opioid receptors), promoting the release of pruritogenic molecules (including opioids, proteases, substance P, nerve growth factor, neutrotrophin 4, endocannabinoids). In addition, keratinocytes can release acetylcholine directly stimulating sensory nerves as well as lowering their threshold for stimuli activation (Mollanazar et al., 2016). Keratinocytes, therefore, can be stimulated by, and secrete, pruritic factors as well as communicate the itch sensation downstream.
Cytokines are critical components in the pathogenesis of atopic dermatitis with some also playing an important role in atopic itch.
Intradermal injection of IL-2 into patients with atopic dermatitis or healthy controls induced itching and erythema for 48–72 hours (Wahlgren et al., 1995). This link between IL-2 and itch has also been observed in patients receiving intravenous IL-2 as a cancer therapy with severe pruritus a recognised side effect (Gaspari et al., 1987; Lee et al., 1988; Kremer et al., 2014). Calcineurin promotes IL-2 synthesis and secretion (Kremer et al., 2014) and calcineurin inhibition with ciclosporin A was shown to reduce pruritus in patients with atopic dermatitis (Wahlgren et al., 1990).
IL-4 and IL-13 help promote the Th2-driven immune response observed in patients with atopic dermatitis. Levels of both cytokines are increased in lesional skin (Jeong et al., 2003) and IL-13 levels are elevated in the serum of patients with atopic dermatitis where they correlate with disease severity (Metwally et al., 2004). The role of IL-4 and IL-13 in pruritus has been confirmed using a monoclonal antibody that targets the action of both IL-4 and IL-13 (dupilumab), which reduced pruritus severity by over 50% during clinical trials (Beck et al., 2014).
IL-31 expression is elevated in several pruritic conditions including atopic dermatitis, prurigo nodularis and allergic contact dermatitis (Sonkoly et al., 2006; Raap et al., 2008). It signals by binding to its receptor complex, expressed on keratinocytes, epithelial cells and by dorsal root ganglion pruriceptors, promoting transcription via the JAK/STAT pathway (Sonkoly et al., 2006; Kasraie et al., 2013; Kremer et al., 2014). Interestingly, IL-31 has been shown to promote a late onset itch (mean delay 143 minutes) suggesting that it acts via indirect mechanisms (Hawro et al., 2014).
IL-33 is a promoter of Th2-mediated inflammation, a key driver of atopic dermatitis (Kroeger et al., 2009; Rankin et al., 2010; Savinko et al., 2012). Elevated levels have been observed in the lesional skin and serum of patients with atopic dermatitis where serum levels correlated with disease severity (Tamagawa-Mineoka et al., 2014). Little is known about how IL-33 is involved in chronic pruritus, however, recent in vitro data indicates that it promotes Mast cell expression and secretion of IL-31. Interestingly, IL-33-mediated upregulation of IL-31 was enhanced by co-stimulation with IL-4, substance P and IgE (Mollanazar et al., 2016; Petra et al., 2018).
TSLP is an important mediator of T cell maturation and activation and is believed to be a key driver of atopic dermatitis initiation and maintenance (Moniaga et al., 2013; Wilson et al., 2013; Ziegler et al., 2013). Its expression is upregulated in keratinocytes in atopic dermatitis (Jariwala et al., 2011) helping to promote Th2-mediated inflammation. TSLP is also a pruritogenic molecule that can promote itch directly via cutaneous sensory neurons (Wilson et al., 2013).
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